Front. Mol. Biosci. Frontiers in Molecular Biosciences Front. Mol. Biosci. 2296-889X Frontiers Media S.A. 1077968 10.3389/fmolb.2022.1077968 Molecular Biosciences Review A review on the role of miR-671 in human disorders Ghafouri-Fard et al. 10.3389/fmolb.2022.1077968 Ghafouri-Fard Soudeh 1 Askari Arian 2 Hussen Bashdar Mahmud 3 4 Rasul Mohammed Fatih 5 Hatamian Sevak 6 Taheri Mohammad 7 8 * Kiani Arda 9 * 1 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 3 Department of Biomedical Sciences, Cihan University-Erbil, Kurdistan Region, Iraq 4 Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq 5 Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Iraq 6 Department of Anesthesia, Shahid Madani Hospital, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran 7 Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 8 Institute of Human Genetics, Jena University Hospital, Jena, Germany 9 Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

Edited by: Wei Ye, Guangdong Academy of Science, China

Reviewed by: Meredith Tennis, University of Colorado Denver, United States

Guan Wang, Sichuan University, China

 *Correspondence: Mohammad Taheri, Mohammad.taheri@uni-jena.de; Arda Kiani, ardakiani@sbmu.ac.ir

This article was submitted to RNA Networks and Biology, a section of the journal Frontiers in Molecular Biosciences

 05 12 2022 2022 9 1077968 23 10 2022 25 11 2022 Copyright © 2022 Ghafouri-Fard, Askari, Hussen, Rasul, Hatamian, Taheri and Kiani. 2022 Ghafouri-Fard, Askari, Hussen, Rasul, Hatamian, Taheri and Kiani

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miR-671 is encoded by a gene on 7q36.1 and contributes to the pathogenesis of a variety of disorders, including diverse types of cancers, atherosclerosis, ischemic stroke, liver fibrosis, osteoarthritis, Parkinson’s disease, rheumatoid arthritis, acute myocardial infarction and Crohn’s disease. In the context of cancer, different studies have revealed opposite roles for this miRNA. In brief, it has been shown to be down-regulated in pancreatic ductal carcinoma, ovarian cancer, gastric cancer, osteosarcoma, esophageal squamous cell carcinoma and myelodysplastic syndromes. Yet, miR-671 has been up-regulated in glioma, colorectal cancer, prostate cancer and hepatocellular carcinoma. Studies in breast, lung and renal cell carcinoma have reported inconsistent results. The current review aims at summarization of the role of miR-671 in these disorders focusing on its target mRNA in each context and dysregulated signaling pathways. We also provide a summary of the role of this miRNA as a prognostic factor in malignancies.

 mir-671 cancer biomarker expression prognostic Introduction

microRNAs (miRNAs) are small-sized non-coding RNAs that partake in the post-transcriptional regulation of gene expression through influencing the stability and translation of transcripts. They are transcribed by RNA polymerase II. The pri-miRNAs produced by this enzyme is capped and polyadenylated. This transcript undergoes a series of cleavage by the Drosha and cytoplasmic Dicer ribonuclease enzymes to produce the stem-loop precursor miRNA and mature miRNA, respectively. The latter is embraced into a RNA-induced silencing complex which can recognize target mRNAs and suppress its translation or destabilize it (Macfarlane and Murphy, 2010). miRNAs participate in the pathoetiology of several disorders through modulation of expression of genes (Hussen et al., 2021), altering signaling pathways (Hussen et al., 2022) or interactions with other types of non-coding RNAs (Ghafouri-Fard et al., 2021a; Taheri et al., 2022).

miR-671 is encoded by a gene on 7q36.1 and involved in the pathogenesis of a range of disorders, including diverse types of cancers, atherosclerosis, ischemic stroke, liver fibrosis, osteoarthritis, Parkinson’s disease, rheumatoid arthritis, acute myocardial infarction and Crohn’s disease. There is not sufficient data about the role of this miRNA in normal physiological processes. However, differential expression of this miRNA in the visceral adipose tissues of patients with non-alcoholic fatty liver disease (Estep et al., 2010) indicates its possible role in metabolic pathways. Moreover, miR-671 has been shown to down-regulate the CDR1 (Cerebellar Degeneration-Related protein 1) gene through an Ago2-slicer-dependent mechanism (Hansen et al., 2011). Moreover, this miRNA has been found to be mainly localized in the nucleus (Hansen et al., 2011). There is no clear evidence about differential expression or functional roles of miR-671-3p versus miR-671-5p. The current review aims at summarization of the role of miR-671 in these disorders focusing on its target mRNA in each context and dysregulated signaling pathways. We also provide a summary of the role of this miRNA as a prognostic factor in malignancies.

miR-671 in cancers

The influence of miR-671 in the carcinogenesis has been valued by a number of studies in cancer cell lines, animal models of cancers and samples obtained from affected individuals. In the succeeding sections, we define the role of miR-671 in the carcinogenesis based on these three lines of evidence.

 Cell line studies Up-regulation of miR-671 in cancer cell lines

Studies in colorectal cancer cell lines have shown down-regulation of circ_PTPRA. Exosomal circ_PTPRA has been shown to induce cell cycle arrest and inhibit proliferation of colorectal cancer cells. In addition, exosomal circ_PTPRA could promote sensitivity of these cells to radiation, resulting in inhibition of colony formation and induction of apoptosis. Mechanistically, circ_PTPRA functions as a sponge for miR-671-5p to increase SMAD4 levels. Taken together, circ_PTPRA inhibits growth and radioresistance of colorectal cancer cells through down-regulation of miR-671-5p levels. Moreover, suppression of miR-671-5p has also blocked growth and radioresistance of these cells through enrichment of expression of SMAD4 (Yang et al., 2022b). Another study in this type of cancer has shown overexpression of a circular RNA, namely circGLIS2. This circRNA is sponged by miR-671. Over-expression of circGLIS2 has led to activation of NF-ƙB pathway and induction of production of pro-inflammatory chemokines leading to stimulation of tumor-associated inflammatory responses via recruitment of leukocytes. Taken together, circGLIS2 activates NF-ƙB signaling and promotes migratory ability of colorectal cancer cells through adsorbing miR-671 (Figure 1) (Chen et al., 2020a). Another functional study in colorectal cancer cells has shown the effect of miR-671-5p up-regulation in enhancement of cell proliferation, migratory capacity, and invasiveness of these cells, whereas its downregulation has led to reverse effects. Therefore, miR-671-5p has been suggested as an oncogenic miRNA in colon cancer which exerts its effects through targeting Tripartite Motif Containing 67 (TRIM67) (Jin et al., 2019), a gene, that is, possibly involved in zinc ion binding activity, regulation of protein localization and negative regulation of Ras protein signal transduction (https://www.genecards.org/cgi-bin/carddisp.pl?gene=TRIM67).

The illustration shows signaling pathways underlying the role of miRNA-671 is as a tumor suppressor miRNA in cancers. miRNA-671 inhibits many signaling pathways and carcinogenic mRNAs, resulting in increased apoptosis while lowering proliferation, migration, and invasion of cancer cells.

miR-671-3p has also been shown to exert oncogenic roles in glioma cells through targeting CKAP4 (Lu et al., 2018). Moreover, it has been demonstrated to be sponged by the tumor suppressor circRNA circDLC1 in these cells (Wu et al., 2022a). A single study in lung cancer cells has shown that miR-671-3p enhances progression of lung cancer through blocking expression of FOXP2 expression in lung cancer (Li et al., 2019b), thus referring to an oncogenic role for this miRNA in lung cancer.

Two independent studies in glioblastoma cell lines have revealed that miR-671-5p has transforming roles. Firstly, more than two-fold upregulated levels of miR-671-5p reduced levels of CDR1-AS/VSNL1 in glioblastoma cell lines A172, CAS-1 and DBTRG. This phenomenon is associated with increased migration and proliferation (Barbagallo et al., 2016). In another study it was demonstrated that if upregulated, miR-671-5p has oncogenic roles, but with competing endogenous features of Circular RNA circ_0001946, this miRNA is suppressed and its suppression is in favor of benign properties (Li and Diao, 2019).

Prostate cancer related bioinformatics analysis has shown that miR-671-5p is amongst top differentially expressed miRNAs (Zhu et al., 2020). miR-671-5p has a binding site on the 3′-UTR region of NFIA (Zhu et al., 2020). According to Yang et al., NFIA acts as a tumor suppressor gene in glioma and squamous carcinoma (Yang et al., 2018). Upregulation of miR-671-5p in prostate cancer cell lines reduces NFIA/CRYAB levels and contributes to malignant features like increased proliferation, migration and invasion (Figure 2) (Zhu et al., 2020).

The above illustration shows the roles of miRNA-671, which acts as an oncogene and stimulates cancer growth in several types of cancer. MiRNA-671 can target different tumor suppressor mRNAs and, through inhibition of translation, increase proliferation, migration, and invasion of cancer cells.

In kidney cancers category, miR-671-5p has been shown to be overexpressed patterns in clear cell renal cell carcinoma (ccRCC) cell lines (786-O and CAKI-1) (Chi et al., 2020). Its overexpression is regulated by HMGA1, which involves in chromatin remodeling (Chiefari et al., 2018). Upregulated levels of miR-671-5p targets APC (a tumor suppressor gene) and gives rise to invasiveness of ccRCC cells (Chi et al., 2020).

 Down-regulation of miR-671 in cancer cell lines

The lncRNA PACERR that sponges miR-671 has been shown to increase the number of M2-polarized cells and enhance proliferation, invasiveness and migration of pancreatic cancer cells. From a mechanistical point of view, PACERR has a role in activation of KLF12/p-AKT/c-myc pathway through sponging miR-671-3p. In fact, this lncRNA is regarded as a regulator of tumor-associated macrophages in pancreatic ductal carcinoma microenvironment (Liu et al., 2022b). Moreover, circ_0092314 has been identified as another non-coding RNA that sponges miR-671 in pancreatic cancer cells, thus increasing expression of S100P and inducing epithelial-mesenchymal transition (EMT) (Shen et al., 2021). These two studies have designated a tumor suppressor effect for miR-671 in pancreatic cancer.

The miR-671-sponging circRNA Circ_0001946 has been shown to be over-expressed in tamoxifen resistant breast cancer cells. This circRNA has been shown to be activated by YY1 in these cells. miR-671-5p mimics could partially reverse the effects of circ_0001946 up-regulation in enhancement of proliferation and invasive properties of drug-resistant breast cancer cells. EGFR has been shown to be the downstream target of miR-671-5p in these cells (Gao et al., 2022). Another study has shown the sponging effect of circSLC8A1 on miR-671 and the impact of this miRNA in the regulation of PTEN/PI3k/AKT pathway (Zhu et al., 2021). Moreover, miR-671-3p has been shown to suppress proliferation and invasiveness of breast cancer cells through modulation of expression of the MTOR-interacting protein DEPTOR (Xia et al., 2020).

Lung cancer cells have also been the subject of functional studies on the role of miR-671. As an example of these studies, Liu et al. (2022a) have shown that the oncogenic role of circRIP2 in this type of cancer is exerted through sequestering miR-671-5p and increasing expression of FOXM1. Moreover, miR-671-5p has been found to inhibit proliferation, migration and invasive aptitude of lung cancer cells through targeting MFAP3L (Ye et al., 2022).

In esophageal squamous cell carcinoma cell lines (including different subtypes of KYSE), elevated levels of FGFR2 activates ERK and AKT signaling pathway and contributes to the malignancy (Li et al., 2019a). Interestingly, miR-671-5p level has shown to be downregulated, hence acting as a tumor suppressor (Li et al., 2019a). Forced expression of this miRNA contributes to diminished levels of FGFR phosphorylation, thus reversing malignant features like proliferation and migration (Li et al., 2019a).

Downregulated levels of miR-671 have also been shown in gastric cancer. In a study conducted by Qiu et al. (2018), reduced level of miR-671-5p has been demonstrated in MKN28 cells compared with normal gastric cells, suggesting an anti-tumor role. Elevating its expression yields decreased ratio of Bcl-2/Bax (increase in BAX), thus promoting apoptosis (Qiu et al., 2018). miR-671-5p targets URGCP and inhibits its expression in MKN28 cells (Qiu et al., 2018). Considering the roles of Up regulator Of Cell Proliferation (URGCP) in the carcinogenesis (Xie et al., 2012; Cai et al., 2015), there is no surprise that targeting it by miR-671-5p has shifted MKN28 cells to normal cell features (Qiu et al., 2018).

Detailed information about the roles of miR-671 in different cancer cell lines is shown in Table 1.

Function of miR-671 in cancer cell lines (Arrows indicate the effects of changes in the expression of mentioned genes (either endogenous or exogenous). ∆: knockdown or downregulation, MPP+: 1-methyl-4-phenylpyridinium).

Tumor type microRNA type Levels in cancer cell lines compared with normal cell lines Interactions Downstream target of miRNA Effect of miR-671 up-regulation on its target Cell line Associated phenotypes with dysregulation of miR-671 References
Colorectal cancer miR-671-5p Upregulated circ_PTPRA/SMAD4 SMAD4 Inhibition HCT116 and DLD1 ↑ circ_PTPRA: ↓ miR-671-5p ↑ SMAD4: ↓ cell growth ↑ sensitivity to radiation Yang et al. (2022b)
miR-671 Downregulated (by GLIS2) GLIS2/NF-ƙB NF-ƙB signaling Inhibition DLD1, HCT-8, HCT116, RKO, HT-29 and HCT-15 ↑ GLIS2: ↓ miR-671-5p ↑ NF-ƙB ↑ migration ↑ motility Chen et al. (2020a)
miR-671-5p Upregulated TRIM67 TRIM67 Inhibition SW480, SW620, LOVO, HCT116 ↑ miR-671-5p: ↓ TRIM67 ↑ proliferation ↑ migration ↑ invasion Jin et al. (2019)
Pancreatic ductal adenocarcinoma miR-671-3p Downregulated (By PACERR) PACERR/KLF12/p-AKT/c-myc KLF12 Inhibition THP-1 and PATU-8988 ↑ PACERR: ↓ miR-671-3p: ↑ KLF12/p-AKT/c-myc ↑ cell invasion ↑ migration Liu et al. (2022b)
miR-671 Downregulated circ_0092314/S100P SP100P Inhibition AsPC-1, BxPC-3, SW-1990 and PaCa-2 ↑ circ_0092314: ↓ miR-671: ↑ S100P ↑ EMT ↑ invasion Shen et al. (2021)
Glioma miR-671-5p Upregulated circDLC1/CTNNBIP1 CTNNBIP1 Inhibition T98G, LN229, A172, and LN18 ↑ circDLC1: ↓ miR-671-5p ↑ CTNNBIP1 ↓ proliferation Wu et al. (2022a)
miR-671-3p Upregulated CKAP4 CKAP4 Inhibition ↑ miR-671-3p: ↓ CKAP4 ↑ proliferation ↑ migration Lu et al. (2018)
Breast cancer miR-671-5p Downregulated (by Circ_0001946) Circ_0001946/EGFR EGFR Inhibition MDA-MB-231 and MDA-MB-436 ↑ Circ_0001946: ↓ miR-671-5p ↑ EGFR ↑proliferation, ↑ resistance to tamoxifen Gao et al. (2022)
miR-671 Upregulated circSLC8A1/KLF16 PTEN/PI3k/Akt KLF16 Inhibition MCF7, T47D, BT474 and MDA-MB-231 ↓ circSLC8A1: ↑ miR-671 ↓ PTEN ↑ PI3k/Akt: ↑ proliferation ↑ migration ↑ invasion Zhu et al. (2021)
miR-671-3p Downregulated DEPTOR DEPTOR Inhibition MCF-7, MDA-MB-231, SK-BR-3 ↑ miR-671-3p: ↓ DEPTOR ↓ invasion ↓ migration ↓ viability Xia et al. (2020)
miR-671-5p Downregulated FOXM1 FOXM1 Inhibition 21T ↑ miR-671-5p: ↓ FOXM1 ↓ proliferation ↓ migration ↓ invasion ↓ chemoresistance Tan et al. (2019)
miR-671-3p Downregulated HNRNPA2/B1 - - MCF-7 ↑ HNRNPA2/B1: ↓ miR-671-3p Klinge et al. (2019)
miR-671-3p - Wnt - - MDA-MB-231 ↑ miR-671-3p: ↓ proliferation ↑ apoptosis Xiong et al. (2018)
miR-671 Upregulated in drug resistant cell lines - - - MDA-MB-231 Drug resistant cell lines exhibited up-regulation of miR-671 Chen et al. (2016)
miR-671-5p Downregulated FOXM1 FOXM1 Inhibition MDA-MB-231, Hs578T, SKBR3, BT-20, MDA-MB-468, MCF-7, and T47D ↑ miR-671-5p: ↓ FOXM1 ↓ proliferation ↓ migration ↓ EMT ↑ sensitivity to chemotherapy Tan et al. (2016)
Ovarian cancer miR-671-5p - HDAC5/HIF-1α HDAC5 & HIF-1α Inhibition H8910 ↑ miR-671-5p: ↓ HDAC5/HIF-1α: ↓ proliferation ↓ migration ↓ invasion ↑ apoptosis Peng et al. (2022)
Non-small cell lung cancer miR-671-5p Downregulated (by CircRIP2) CircRIP2/FOXM1 FOXM1 Inhibition A549, H460 and HCC827 ↑ CircRIP2: ↓ miR-671-5p ↑ FOXM1 ↑ proliferation ↑ migration Liu et al. (2022a)
miR-671-5p Downregulated MFAP3L MFAP3L Inhibition H1299, 95D and A549 ∆ miR-671-5p: ↑ MFAP3L ↑ proliferation ↑ migration ↑invasion Ye et al. (2022)
miR-671-3p Upregulated FOXP2 FOXP2 Inhibition A549 and H1975 ∆ miR-671-3p: ↑ FOXP2 ↓ proliferation ↑ apoptosis Li et al. (2019b)
miR-671-3p Downregulated CCND2 CCND2 Inhibition A549, H1299, H1650 and H1975 ↑ miR-671-3p: ↓ CCND2 ↓ proliferation ↓ invasion Yao et al. (2019)
Lung adenocarcinoma miR-671-5p - C8orf34-as1/MFAP4 C8orf34-as1 and MFAP4 Inhibition A549 and H1299 ↑ miR-671-5p: ↓ MFAP4 ↑ tumor formation Han et al. (2021)
Lung squamous carcinoma miR-671–5p Downregulated CDR1as/CDR1 CDR1as Inhibition SK-MES-1 and H520 ↑ miR-671–5p: ↓ CDR1as ↓ metastasis Harrison et al. (2020)
Gastric cancer miR-671-5p Downregulated Circ_0000620/MMP2 MMP2 Inhibition HGC27 and AGS ↑ Circ_0000620: ↓ miR-671-5p ↑ MMP2 ↑ proliferation ↑ invasion Ren et al. (2021)
miR-671-5p Downregulated (by CircPIP5K1A) CircPIP5K1A/KRT80/PI3K/AKT KRT80 Inhibition MKN45, AGS, BGC823, MGC803 and SGC7901 ↑ CircPIP5K1A: ↓ miR-671-5p ↑ KRT80/PI3K/AKT ↑ proliferation ↑ Invasion ↑ migration ↑ EMT Song et al. (2020)
miR-671-5p Downregulated URGCP URGCP Inhibition MKN28 ↑ miR-671-5p: ↓ URGCP ↓ proliferation ↑ apoptosis Qiu et al. (2018)
Glioblastoma miR-671-5p Downregulated MSI1/STAT3/TRAF2 STAT3 Inhibition Hs683, SW1783, U251, and U87 GBM ↑ MSI1: ↓ miR-671-5p: ↑ STAT3 ↑ TRAF2 ↑ proliferation ↓ radiation sensitivity ↑ cancer stem cell features Lin et al. (2021)
miR-671-5p Upregulated circ_0001946/CDR1 CDR1 Inhibition U87 and U251 cells ↑ circ_0001946: ↓ miR-671-5p ↑ CDR1 ↑ apoptosis ↓ migration ↓ invasion Li and Diao, (2019)
miR-671-5p Upregulated CDR1-AS/CDR1/VSNL1 CDR1-AS and VSNL1 Inhibition A172, CAS-1, DBTRG, HCT-116, SK-N-BE, SNB-19, U-87 MG ↑ miR-671-5p: ↓ CDR1-AS/VSNL1 ↑ migration ↑ proliferation Barbagallo et al. (2016)
Papillary thyroid carcinoma miR-671-5p - TRIM14 TRIM14 Inhibition IHH-4 and TPC-1 ↑ miR-671-5p: ↓ TRIM14 ↓ viability ↓ colony formation ↓ migration ↓ invasion Wang et al. (2021c)
Osteosarcoma miR-671-5p Downregulated SMAD3 SMAD3 Inhibition hFOB1.19, MG63, U2OS and Saos-2 ↑ miR-671-5p: ↓ SMAD3 ↓ EMT ↓ invasion Hu et al. (2021)
miR-671-5p Downregulated TUFT1 TUFT1 Inhibition Saos-2, U2OS, and MG-63 ↑ miR-671-5p: ↓ TUFT1 ↓ viability ↓ migration ↓ invasion Ma et al. (2020)
miR-671-5p Downregulated DLEU1/DDX5 DDX5 Inhibition HOS, MG63, U2OS, and Saos-2 ↑ DLEU1: ↓ miR-671-5p ↑ DDX5 ↑ proliferation ↑ migration ↑ invasion Chen et al. (2019b)
miR-671-5p Downregulated CCND1/CDC34 CCND1/CDC34 Inhibition U2OS, HOS, Saos-2, MNNG/HOS CI #5, and MG-63 ↑ miR-671-5p: ↓ CCND1/CDC34 ↓ proliferation Xin et al. (2019)
Prostate cancer miR-671–5p Upregulated NFIA/CRYAB NFIA Inhibition RWPE-1, LNCaP, PC-3M, 22RV-1, and C4-2 ↑ miR-671–5p: ↓ NFIA/ CRYAB:↑ proliferation ↑ migration ↑ invasion Zhu et al. (2020)
miR-671 Upregulated with treatment SOX6 SOX6 Inhibition 22RV1, DU145, Tsu-Pr1, LNCAP and PC3 ↑ miR-671:↓ SOX6↑ proliferation Yu et al. (2018)
Human cutaneous malignant melanoma miR-671-5p Upregulated with treatment Guizhi Fuling Pills/TPT1-AS1 - - A375 Treatment with Guizhi Fuling Pills:↓ TPT1-AS1↑ miR-671-5p↓ proliferation↓ migration↓ invasion Zhang, (2020)
Clear cell renal cell carcinoma miR-671-5p Upregulated HMGA1/APC APC Inhibition 786-O, CAKI-1 ↑ HMGA1:↑ miR-671-5p↓ APC↑ migration↑ invasion↑ EMT Chi et al. (2020)
Oral squamous cell carcinoma miR-671-5p Downregulated (by CircCDR1) CircCDR1as/AKT/ERK ½/mTOR - - ca-8113, SCC-15, and HOK ↑ CircCDR1:↓ miR-671-5p↓ mTOR↑ AKT/ERK ½↑ autophagy↑ viability Gao et al. (2019)
Esophageal squamous cell carcinoma miR-671-5p Downregulated FGFR2/ERK and AKT FGFR2 Inhibition KYSE 510, KYSE 410, KYSE 180, KYSE 140, KYSE 30, HKESC1, EC 18, EC 109, EC 9706 ↑ miR-671-5p: ↓ ERK and AKT ↓ phosphorylation of FGFR2 ↓ proliferation ↓ Colony formation ↓ migration ↓ invasion ↓ tumorigenesis Li et al. (2019a)
Hepatocellular carcinoma miR-671-5p Downregulated (hypoxia induced) HIF-1α/TUFT1/Ca2+/PI3K/AKT TUFT2 Inhibition Hep3B Hypoxia: ↓ miR-671-5p: ↑ TUFT2 ↑ Ca2+/PI3K/AKT ↑ proliferation ↑ metastasis Dou et al. (2019)
Epithelioid sarcoma miR-671-5p - SMARCB1 SMARCB1 Inhibition HT-1080, Caco-2, and HDFa ↑ miR-671-5p: ↓ SMARCB1 Papp et al. (2014)
Animal studies

Different animal studies have been performed to evaluate the impact of miR-671 dysregulation on the course of tumor formation. Moreover, a number of other studies have focused on circRNAs that act as molecular sponges for miR-671. For instance, up-regulation of circ_00923 in pancreatic cancer cells has led to down-regulation of miR-671 in tissues of affected animals and enhancement of tumor growth (Shen et al., 2021). On the other hand, over-expression of circ_0001946 has resulted in reduction of glioma growth in animal models (Li and Diao, 2019) Similar to cell line studies, studies in xenograft models of cancers have indicated different results regarding the oncogenic versus tumor suppressor effect of miR-671 (Table 2). For instance, in pancreatic cancer models, down-regulation of miR-671 has been associated with enhancement of tumor growth (Shen et al., 2021). Similar results have been obtained in xenograft models of ovarian cancer (Peng et al., 2022). On the other hand, studies in animal models of colorectal cancer have reported opposite results (Yang et al., 2022b). Detailed information about the role of miR-671 in animal models of cancer is presented in Table 2.

Effect of miR-671 in cancer development based on research in animal models. (∆: knockdown or downregulation).

Tumor type microRNA type Animal models Types of manipulation and engrafted cells Associated phenotypes with dysregulation of miR-671 References
Pancreatic ductal adenocarcinoma miR-671 Nude mice Subcutaneous injection of PaCa-2 cells transfected with specific siRNA against circ_0092314/AsPC-1 cells transfected with circ_0092314 overexpression plasmid ↑ circ_0092314: ↓ miR-671 ↑ tumor growth Shen et al. (2021)
Glioma miR-671-5p BALB/c nude mice Subcutaneous injection of LN229 cells stably overexpressing METTL3 (lentiviral LV-oe-METTL3) ↑ METTL3: ↓ miR-671-5p ↓ tumor growth Wu et al. (2022a)
miR-671-5p BALB/c nude mice Subcutaneous injection of U87 cells transfected with circ_0001946 ↑ circ_0001946: ↓ miR-671-5p ↓ tumor growth Li and Diao, (2019)
Glioblastoma miR-671-5p BALB/c nude mice U87MG cells transplantation into the brain which were transfected with miR-671-5p mimics ↑ miR-671-5p: ↓ tumor growth Lin et al. (2021)
Ovarian cancer miR-671-5p BALB/c nude mice - ∆ miR-671-5p: ↑ tumor growth Peng et al. (2022)
Colorectal cancer miR-671-5p BALB/c nude mice Subcutaneous injection of vector transfected HCT116 cells with circ_PTPRA ↑ circ_PTPRA ↓ miR-671-5p: ↓ tumor growth ↓ resistance to radiation Yang et al. (2022b)
Papillary thyroid carcinoma miR-671-5p BALB/c nude mice Subcutaneous injection with TPC-1 cells stably transfected with pMIRNA-miR-671-5p (lentiviral) ↑ miR-671-5p: ↓ tumor growth Wang et al. (2021c)
Breast cancer miR-671 BALB/c nude mice Subcutaneous injection with MCF7 or T47D containing miR-671 inhibiting vectors ↓ miR-671: ↓ tumor growth Zhu et al. (2021)
Lung squamous carcinoma miR-671-5p Athymic nude mice Intravenous injection with overexpressing miR-671-5p H520 cells ↑ miR-671-5p: ↓ metastasis Harrison et al. (2020)
Prostate cancer miR-671-5p BALB/c nude mice Subcutaneous injection with PC-3/LV-in-miR-671 (lentiviral) ∆ miR-671-5p: ↓ tumor growth Zhu et al. (2020)
Clear cell renal cell carcinoma miR-671-5p BALB/c nude mice Intravenous injection with 786-O cells containing miR-671-5p mimics ↑ miR-671-5p: ↑ tumor metastasis Chi et al. (2020)
Oral squamous cell carcinoma miR-671-5p BALB/c nude mice Subcutaneous injection with Tca-8113 transfected with circCDR1as lentivirus ↑ circCDR1: ↓ miR-671-5p ↑ tumor growth Gao et al. (2019)
Osteosarcoma miR-671-5p BALB/c nude mice Subcutaneous injection with MNNG/HOS Cl #5 cells (transfected with miR-671-5p) ↑ miR-671-5p: ↓ tumor size Xin et al. (2019)
Esophageal squamous cell carcinoma miR-671-5p BALB/c nude mice Subcutaneous injection with KYSE180 cells transfected with miR-671-5p mimics ↑ miR-671-5p: ↓ tumor size Li et al. (2019a)
Studies in human samples

Expression of miR-671-5p has been increased in colon cancer tissues. Notably, up-regulation of miR-671-5p in this type of cancer has been associated with involvement of lymph nodes, TNM stage, and low overall survival time of affected individuals (Jin et al., 2019). In tumor associated macrophages of pancreatic cancer patients, the lncRNA PACERR that sponges miR-7671 has been shown to be over-expressed in association with poor prognosis of patients (Liu et al., 2022b).

Studies in clinical samples of breast cancer have reported different results regarding the expression of miR-671. First, the miR-671-sponging circRNA circ_0001946 has been shown to be over-expressed in breast cancer tissues, leading to down-regulation of miR-671 (Gao et al., 2022). Although two other studies have reported down-regulation of miR-671-3p (Xiong et al., 2018) and miR-671-5p (Tan et al., 2016) in breast cancer samples, another study has demonstrated up-regulation of miR-671 in another cohort of breast cancer patients (Zhu et al., 2021).

Several studies have shown the impact of miR-671 dysregulation on survival of patients with different kinds of cancer, including ovarian, colorectal and lung cancers as well as osteosarcoma (Table 3). However, a single study in breast cancer patients has reported lack of association between expression levels of miR-671 and median survival of patients (Xiong et al., 2018). Moreover, abnormal expression of miR-671 has been associated with tumor size, TNM stage or metastasis in some kind of cancers, such as colorectal cancer (Jin et al., 2019), lung cancer (Ye et al., 2022) and renal cell carcinoma (Chi et al., 2020). In prostate cancer, up-regulation of miR-671-5p has been associated with higher Gleason score, and BCR status and poor prognosis, but not with tumor stage and lymph node metastasis (Zhu et al., 2020).

Abnormal levels of miR-671 in clinical specimens.

Tumor type microRNA type Samples Expression (tumor vs. normal) Kaplan-Meier and Cox regression analyses (Impact of miR-671 dysregulation) Association of miR-671 levels with clinicopathologic features Reference
Pancreatic ductal adenocarcinoma (PDAC) miR-671-3p 46 PDAC tissues + paired ANT Downregulated Upregulation is associated with better prognosis - Liu et al. (2022b)
miR-671 40 PDAC tissues + paired ANT Downregulated Downregulation is associated with poor prognosis - Shen et al. (2021)
Glioma miR-671-5p 40 glioma tissues + paired ANT Upregulated - - Wu et al. (2022a)
miR-671-3p 8 glioma tissues + paired ANT Upregulated - - Lu et al. (2018)
Breast cancer (BC) miR-671-5p 56 BC tissues + paired ANT Downregulated - - Gao et al. (2022)
miR-671 77 BC tissues + paired ANT Upregulated - - Zhu et al. (2021)
miR-671-3p 38 BC tissues + paired ANT + 11 GEO datasets Downregulated Upregulation had no effect on median survival - Xiong et al. (2018)
miR-671-5p 30 IDC tissues + paired ANT Downregulated - - Tan et al. (2016)
Ovarian cancer (OC) miR-671-5p 92 OC tissues + paired ANT Downregulated Downregulation is associated with poor prognosis - Peng et al. (2022)
Colorectal cancer (CRC) miR-671-5p 25 CRC tissues+ 10 healthy controls Upregulated Upregulation is associated with poor prognosis - Yang et al. (2022b)
miR-671-5p 115 CRC tissues + paired ANT Upregulated Upregulation is associated with poor prognosis/low O-S lymph node metastasis and TNM stage Jin et al. (2019)
miR-671-5p 38 rectal cancer patients (exposed to capecitabine-oxaliplatin and radiotherapy) Upregulated in TRG1 patients - - Della Vittoria Scarpati et al. (2012)
Non-small cell lung cancer (NSCLC) miR-671-5p 30 NSCLC tissues + paired ANT Downregulated - - Liu et al. (2022a)
miR-671-5p 56 NSCLC tissues + paired ANT Downregulated - advanced TNM stage and lymph node metastasis Ye et al. (2022)
miR-671-3p 43 NSCLC tissues + paired ANT Downregulated - tumor size, TNM stage and metastasis Yao et al. (2019)
miR-671-3p 40 NSCLC tissues + paired ANT Upregulated - - Li et al. (2019b)
Lung adenocarcinoma miR-671-5p TCGA database High mRNA expression-based stemness index is associated with higher miR-671-5p - - Han et al. (2021)
miR-671-3p 72 lung adenocarcinoma tissues including: 19 EGFR-mutated +17 KRAS-mutated + 16 ALK-rearranged + 20 triple negative cancers Downregulated in ALK-rearranged cases - - Kim et al. (2017)
Lung squamous cell carcinoma (LUSC) miR-671 478 LUSC tissues + 45 paired ANT Upregulated Upregulation is associated with high O-S - Chen et al. (2019a)
Gastric cancer (GC) miR-671-5p 44 GC tissues + paired ANT Downregulated - - Ren et al. (2021)
miR-671-5p 25 GC tissues + paired ANT Downregulated - - Song et al. (2020)
miR-671-5p 30 GC tissues + paired ANT Downregulated - - Qiu et al. (2018)
Osteosarcoma (OS) miR-671-5p GSE28423 GSE70414 Datasets Downregulated - - Hu et al. (2021)
miR-671-5p GSE28423 GSE28424 Datasets Downregulated Downregulation is associated with poor prognosis - Ma et al. (2020)
miR-671-5p 50 OS Tissues + paired ANT Downregulated - - Chen et al. (2019b)
miR-671-5p 20 OS tissues + paired ANT + GSE28425 Downregulated Downregulation is associated with low O-S - Xin et al. (2019)
Prostate cancer (PCa) miR-671-5p 25 PPCa tissues + 15 MPCa tissues + 13 ANT + GSE21032 GSE21036 GSE21034 Upregulated Upregulation is associated with higher Gleason score, and BCR status and poor prognosis. miR-671-5p is an independent factor for predicting BCR-free survival Not associated with tumor stage and lymph node metastasis Zhu et al. (2020)
miR-671-3p 66 PCa tissues + 60 healthy controls + 8 controls with atypical lesion Upregulated in black cases - - McDonald et al. (2018)
miR-671 8 PCa tissues + paired ANT Upregulated - - Yu et al. (2018)
miR-671-5p GSE21032 dataset Upregulated - - Sadeghi et al. (2016)
Renal cell carcinoma (RCC) miR-671-3p 13 lRCC tissues + 15 mRCC Downregulated in metastatic tissues - - Zhu et al. (2016)
Clear cell renal cell carcinoma (ccRCC) miR-671-5p 90 ccRCC tissues + paired ANT Upregulated Upregulation is associated with poor prognosis/low O-S. miR-671-5p is an independent prognostic factor for O-S advanced TNM stage Chi et al. (2020)
miR-671 TCGA database Upregulated in Mutant BAP1 tumors Upregulation is associated with poor prognosis/low O-S - Ge et al. (2017)
Chordomas miR-671-5p 7 chordomas with INI1 loss + 12 normal chordomas + 3 nucleolus pulposus (control) Downregulation of SMARCB1/INI1 results in upregulation of miR-671-5p - - Malgulwar et al. (2017)
Glioblastoma multiforme (GBM) miR-671-5p 45 GBM tissues + 3 healthy tissues Upregulated - - Barbagallo et al. (2016)
Esophageal squamous cell carcinoma (ESCC) miR-671-3p 56 ESCC tissues + paired ANT Downregulated - - Warnecke-Eberz et al. (2015)
Epithelioid sarcoma miR-671-5p 30 epithelioid sarcoma tissues + 2 rhabdoid tumor tissues + 2 SMARCB11 epithelioid sarcoma tissues + 3 epithelioid sarcoma with biallelic-deleted SMARCB1 tissues Upregulated in epithelioid sarcoma tissues - - Papp et al. (2014)
Hepatocellular carcinoma (HCC) miR-671-5p 265 HCC patients + 354 CHB patients + 205 healthy controls Upregulated in HCC patients - - Sun et al. (2013)
Prolactinoma miR-671-5p 15 prolactinoma patients (5 patients treated with bromocriptine) Downregulated in treated patients - - Wang et al. (2012)
Myelodysplastic syndromes (MDS) miR-671-5p 19 MDS tissues + 8 healthy controls Downregulated - - Borze et al. (2011)

ANT, Adjacent normal tissue; PPCa, Primary localized PCa tissues; MPCa, Metastatic PCa tissues; BCR, Biochemical recurrence; O-S, Overall survival; lRCC, Localized renal cell carcinoma; mRCC: Metastatic renal cell carcinoma; IDC, Invasive ductal carcinoma; CHB, chronic hepatitis B; TRG1, Tumor regression grade 1.

Association between miR-671 variants and risk of soft tissue sarcomas has been assessed in a population of Chinese patients and healthy controls. The results of this study has shown association between miR-671 rs1870238 GC + CC and miR-671 rs2446065 CG + GG genotypes and risk of this type of tumor after adjustment for age and smoking (Zhang et al., 2022a).

 Non-malignant conditions Cell line studies

Experiments in ox-LDL-treated HUVECs have shown down-regulation of miR-671-5p and up-regulation of circPTPRA expression. These two transcripts have been shown to interact with each other. While circPTPRA silencing has reversed ox-LDL-induced decrease in viability of HUVECs, miR-671-5p downregulation could abolish this effect. Cumulatively, circPTPRA silencing can protect against ox-LDL-associated HUVECs damage through enhancing expression of miR-671-5p (Luo and Zhou, 2022).

Another study has shown that the effects of ANRIL silencing in alleviation of neuroinflammatory responses in ischemia is mediated through influencing the miR-671-5p/NF-κB axis (Figure 3) (Deng et al., 2022). Moreover, miR-671-5p could attenuates neuroinflammation through suppression of NF-κB levels (Deng et al., 2021).

The illustration represents the main functions of miRNA-671 in non-malignant disorders. The level of miRNA-671 expression influences the development of a wide range of disorders by modulation of several signaling pathways.

miR-671-5p expression has been revealed to be reduced in S1P-induced hepatic stellate cells and TGFβ1-activated hepatic sinusoidal endothelial cells. Moreover, its expression has been negatively correlated with levels of Angpt1 and VWF. Mechanistically, miR-671-5p could target Angpt1 and VWF (Yang et al., 2022b).

miR-671-5p has also been shown to facilitate the effect of lncRNA DLEU1 in the regulation of chondrocytes proliferation, inflammatory responses, and degradation of extracellular matrix (Wu et al., 2022b). Moreover, the sponging effect of circ_0043947 on miR-671-5p is involved in the pathoetiology of IL1β-induced chondrocyte damage and pathogenesis of osteoarthritis (He et al., 2022). Table 4 summarizes the role of miR-671 in the pathogenesis of non-malignant conditions based on the results of cell line studies.

Cell line studies showing the role of miR-671 in non-malignant conditions.

Disease type microRNA type Interactions Cell line Associated phenotypes with dysregulation of miR-671 Reference
Atherosclerosis miR-671-5p CircRNA-PTPRA HUVECs ox-LDL treatment: ↑ CircRNA-PTPRA ↓ miR-671-5p progression of disease Luo and Zhou, (2022)
Ischemic Stroke miR-671-5p ANRIL/NF-ƙB OGD/R HT22 ↓ ANRIL: ↑ miR-671-5p ↓ NF-ƙB ↑ cell viability ↓ cell cytotoxicity Deng et al. (2022)
miR-671-5p NF-ƙB OGD/R HT22 ↑ miR-671-5p ↓ NF-ƙB ↓ neuroinflammation Deng et al. (2021)
Liver fibrosis miR-671-5p Angpt1 Primary mouse HSCs ↓miR-671-5p: ↑Angpt1 Regulation of angiogenesis Yang et al. (2022b)
Osteoarthritis (OA) miR-671-5p DLEU1 Human chondrocytes ↑ DLEU1: ↓ miR-671-5p: survival of Chondrocyte, ECM degradation, ↑inflammatory factors Wu et al. (2022b)
miR-671-5p IL-1β/Circ_0043947/RTN3 Human primary chondrocytes ↑ IL-1β: ↑ Circ_0043947 ↓ miR-671-5p ↑ RTN3 ↑inflammation He et al. (2022)
miR-671-5p IL-1β/circ-IQGAP1/TCF4 CHON-001 ↑ IL-1β: ↑ circ-IQGAP1 ↓ miR-671-5p ↑ TCF4 ↑ apoptosis ↑ inflammation Xi et al. (2021)
miR-671 IL-1β/Circ_0114876/TRAF2 CHON-001 ↑ IL-1β: ↑ Circ_0114876 ↓ miR-671 ↑ TRAF2 ↑ inflammation Wang et al. (2021b)
miR-671-3p TRAF3 15 OA+ 15 control Chondrocytes ↑ miR-671-3p: ↓ TRAF3 ↑ matrix ↑ proliferation ↓ inflammation ↓ apoptosis Liu et al. (2019)
miR-671 IL-1β CHON-001 ↑ IL-1β and ↑ miR-671: ↓ inflammation ↓ apoptosis Hou et al. (2019)
Mixed dry eye disease miR-671-5p NONMMUT047964.2/Egr-1 MCECs ↑ NONMMUT047964.2: ↓ miR-671-5p ↑ Egr-1 ↑ inflammation Tang et al. (2022)
Parkinson’s disease miR-671-5p LINC00943//ELAVL1 SK-N-SH MPP + treatment: ↑ LINC00493 ↓ miR-671-5P, ↑ ELAVL1 ↑ apoptosis ↑ toxicity Zhang et al. (2022b)
miR-671 CDR1as/GSK3β PC12 Ex-4 treatment: ↓ CDR1as ↑ miR-671 ↓ phosphorylation of GSK3β ↓ injury Quan et al. (2021)
Rheumatoid arthritis miR-671-5p Circ_0001947/STAT3 RA-FLSs and normal FLSs ↑ Circ_0001947 ↓ miR-671-5p ↑ STAT3 ↑ inflammation ↑ cell migration Yang et al. (2022a)
miR-671-5p Circ-FAM120A/MDM4 RA-FLSs and normal FLSs Paeoniflorin treatment: ↓ Circ-FAM120A ↑ miR-671-5p ↓ MDM4 ↓ Proliferation ↓ migration ↓ invasion ↓ inflammation Ghafouri-Fard et al. (2021b)
miR-671-5p circ-PTTG1IP/TLR4 RA-FLSs and normal FLSs ∆ circ-PTTG1IP: ↑ miR-671-5p ↓ TLR4 ↑ apoptosis ↓ Proliferation ↓ migration ↓ invasion ↓ inflammation Chen et al. (2021)
Podocyte injury miR-671-5p Wnt/β-Catenin Human embryonic kidney 293T cells ↑ Wnt/β-Catenin: ↑ miR-671-5p ↑ Injury Wang et al. (2021a)
Acute myocardial infarction miR-671 TGFBR2/Smad2 CP-M138, CP-M073 ↓ miR-671: ↑ TGFBR2/Smad2 ↑ cardiomyocyte injury Zhan et al. (2021)
Crohn’s disease miR-671 NOD2/NF-ƙB HCT116 ↑ miR-671: ↓ NOD2/NF-ƙB ↓ inflammation Chuang et al. (2014)

ox-LDL, Oxidized low-density lipoprotein; OGD/R, Oxygen glucose deprivation/reperfusion; Ex-4, Exendin-4.

 Animal studies

Expression of miR-671-5p has been down-regulated in the mouse fibrotic liver. Notably, its levels have been negatively correlated with expressions of Angpt1, VWF, sphingosine kinase-1, TGFβ1, HIF1α, HIF2α, and markers of fibrosis. Moreover, expression of miR-671-5p has been lower in hepatic sinusoidal endothelial cells and hepatic stellate cells of CCl4 mice compared with control mice. Administration of miR-671-5p agomir could decrease expressions of Anpgt1 and VWF mRNA and protein levels, and attenuate angiogenesis and fibrosis in the liver of animal models (Yang et al., 2022b). Other investigations in animal models of ischemic stroke, mixed dry eye disease, podocyte injury, acute myocardial infarction and osteoarthritis have verified the role of miR-671 in the pathogenesis of these disorders (Table 5).

Animal studies on the role of miR-671 in non-malignant conditions (MCAO: middle cerebral artery occlusion-reperfusion).

Disease type microRNA type Animal models Results References
Ischemic Stroke miR-671-5p MCAO/R C57/BL6 mice ↓ ANRIL: ↑ miR-671-5p Inhibition of NF-ƙB, Decreased infraction and damaged cells Deng et al. (2022)
miR-671-5p MCAO/R C57/BL6 mice ↑ miR-671-5p: Inhibition of NF-ƙB Decreased inflammation Deng et al. (2021)
Liver fibrosis miR-671-5p Male ICR mice injected with CCL4 ↓miR-671-5p: ↑Angpt1 and VWF Induction of angiogenesis in liver fibrosis Yang et al. (2022b)
Mixed dry eye disease miR-671-5p female C57BL/6J mice ↓miR-671-5p: ↑Egr-1 Increased inflammation Tang et al. (2022)
Podocyte injury miR-671-5p BALB/c mice/male CD-1 mice ↑ miR-671-5p: Aggravation of glomerular sclerotic and renal fibrosis Wang et al. (2021a)
Acute myocardial infarction miR-671 C57BL/6JNifdc mice ↓ miR-671: ↑ inflammation ↑ apoptosis ↑ fibrosis Zhan et al. (2021)
Osteoarthritis miR-671 C57BL/6 male wild-type mice ↑ miR-671: ↓ progression of disease Hou et al. (2019)
Studies in human samples

A high throughput sequencing study in pseudoexfoliation syndrome has led to identification of four aberrantly expressed miRNAs among them being miR-671-3p (Tomczyk-Socha et al., 2022). miR-671-5p has also been among miRNAs participating in the pathogenesis of periodontitis through establishment of ceRNA regulatory network regulating autophagy (Bian et al., 2022). miR-671 has also been found to be down-regulated in patients with rheumatoid arthritis (Tang et al., 2019), hand, foot, and mouth disease (Lin et al., 2020), placenta accreta spectrum (Chen et al., 2020b), coronary artery disease (Zhong et al., 2020), Parkinson’s disease (Uwatoko et al., 2019) and Kawasaki disease (Zhang et al., 2018). Table 6 shows the detailed information about the role of this miRNA in human diosrders.

Human studies on the role of miR-671 in non-malignant conditions.

Disease type microRNA type Number of clinical samples Expression (case vs. control) Expression assays References
Atherosclerosis (AS) miR-671-5p 30 AS patients + 30 healthy controls Downregulated Applied Biosystems 7500 Fast Real-Time PCR system Luo and Zhou, (2022)
Liver fibrosis miR-671-5p 20 liver fibrosis patients + 6 healthy controls Downregulated ABIPrism 7300 sequence detecting system Yang et al. (2022b)
Osteoarthritis (OA) miR-671-5p 30 OA patients + 20 controls Downregulated SYBRTM Green kit on ABI7500 PCR System Wu et al. (2022b)
miR-671-5p 32 OA patients + 32 controls Downregulated SYBR Xi et al. (2021)
miR-671 30 OA patients + 20 controls Downregulated SYBR Premix ExTaq at ABI Prism 7500 Wang et al. (2021b)
miR-671-3p 41 early OA patients + 50 late OA patients Upregulated in early OA patients Illumina’s NextSeq 550 system Ali et al. (2020)
miR-671-3p 15 OA patients + 15 controls Downregulated 7900 Real-time system Liu et al. (2019)
miR-671 20 OA patients + 20 controls Downregulated SYBR Green PCR Mix reagent Hou et al. (2019)
miR-671-3p 12 OA patients + 12 controls Downregulated SurePrint G3 Human miRNA, 8X60K platform (microarray) + ABI 7300 Real-Time PCR System Ntoumou et al. (2017)
Pseudo exfoliation syndrome (PEX) miR-671-3p 5 PEX patients + 5 healthy controls Downregulated Illumina MiSeq instrument Tomczyk-Socha et al. (2022)
Periodontitis miR-671-5p GSE10334, GSE16134, and GSE54710 datasets (Validation in 5 periodontitis tissues + 5 adjacent healthy tissues) Upregulated TB Green Premix Ex Taq™ RR420A/LightCycler 480 System Bian et al. (2022)
miR-671-5p GSE54710 dataset Upregulated - Wang et al. (2019)
Rheumatoid arthritis (RA) miR-671-5p 29 RA synovial tissues + 29 normal synovial tissues Downregulated SYBR Premix DimerEraser Yang et al. (2022a)
miR-671 PBMCs of 18 RA patients + PBMCs of 14 healthy controls Downregulated Bio-Rad SYBR Green Super mix Tang et al. (2019)
miR-671-5p 23 RA synovial tissues + 21 normal synovial tissues Downregulated SYBR Ghafouri-Fard et al. (2021b)
miR-671-5p 29 RA synovial tissues + 23 normal synovial tissues Downregulated SYBR Chen et al. (2021)
Atrial fibrillation miR-671-5p GSE31821, GSE41177, GSE79768, and GSE68475 datasets Upregulated - Xiao et al. (2021)
Hand, foot, and mouth disease (HFMD) miR-671-5p GSE85829, GSE94551, GSE52780, and GSE45589 datasets Downregulated - Lin et al. (2020)
miR-671-5p 5ESHFMD + 5 MHFMD + 5 healthy controls in initial phase/18 ESHFMD + 18 MHFMD + 18 healthy controls in validation phase Downregulated Agilent Technologies (microarray)/ABI 7500 Real-Time PCR System Jia et al. (2014)
Placenta accreta spectrum (PAS) miR-671-3p 12 PAS patients + 12 healthy pregnant women in the screening phase/41 PAS patients + 41 healthy pregnant women in the training phase/20 PAS patients + 20 PP patients + 20 PE patients and 20 healthy pregnant women in the validation phase Downregulated TB Green™ Premix Ex Taq™ II Chen et al. (2020b)
Coronary artery disease (CAD) miR-671-3p 80 CAD patients + 20 healthy controls Downregulated LightCycler 480 (Roche) Zhong et al. (2020)
Multiple system atrophy (MSA) miR-671-5p 31 probable MSA-C patients + 30 probable MSA-P patients + 28 healthy controls Downregulated in MSA-P patients 3D-Gene® Human miRNA oligo chip (Ver. 17.0), Applied Biosystem® StepOnePlus™ real time PCR system Uwatoko et al. (2019)
Parkinson’s disease (PD) miR-671-5p 28 PD patients + 28 healthy controls Downregulated 3D-Gene® Human miRNA oligo chip (Ver. 17.0), Applied Biosystem® StepOnePlus™ real time PCR system Uwatoko et al. (2019)
Kawasaki disease miR-671-5p GSE60965 dataset Downregulated - Zhang et al. (2018)
Hepatitis B virus (HBV) infection miR-671-5p 8 immunotolerant + 8 acute viral hepatitis + 16 no fibrosis + 19 early and 14 fibrosis, + 7 healthy controls Upregulated in advance fibrosis Agilent´s human miRNA microarray version V16 Singh et al. (2018)
Blood stasis syndrome (BSS) miR-671-3p BSS patients including: 10 QDBS patients + 10 QSBS patients + 10 CCBS patients + 10 HABS patients + 40 diabetic patients without BSS Upregulated in BSS Patients Hiseq2000 platform and bioinformatics analysis Chen et al. (2018)
Localized cutaneous leishmaniasis (LCL) miR-671 12 LCL patients + 7 healthy controls + GSE55664 and GSE63931 miR-671 levels correlate to a better response to treatment ABI 7500 real-time PCR instrument Nunes et al. (2018)
Obesity miR-671-3p 3 obese patients after LAGB Downregulated TaqMan low density arrays Human MicroRNA Panel v1.0 (microarray) Nardelli et al. (2017)
Graft versus host disease (GVHD) miR-671-3p 19 acute GVHD patients + 38 non-GVHD patients in training phase/21 acute GVHD patients + 33 non-GVHD patients in validation phase Upregulated in acute GVHD TaqMan® Human MicroRNA Array A/GeneAmp(Chen et al., 2020b) PCR System 9700 Zhang et al. (2016)
Intrahepatic cholestasis of pregnancy (ICP) miR-671-3p 10 ICP patients + 10 healthy pregnant women in initial phase/40 ICP patients + 50 healthy pregnant women in validation phase Upregulated in ICP patients ViiA7 Ma et al. (2016)
Non-alcoholic fatty liver disease miR-671-3p 12 non-alcoholic steatohepatitis (NASH) tissues + 12 non-NASH Downregulated in NASH TaqMan miRNA Array v 2.0 Estep et al. (2010)

PE, Pre-eclamptic; PP, Placenta previa; MSA-P, Parkinsonian variant; MSA-C, Cerebellar variant; QDBS, Qi-deficiency and blood stasis syndrome; QSBS, Qi-stagnation and blood stasis syndrome; CCBS, Cold-coagulation and blood stasis syndrome; HABS, Heat-accumulation and blood stasis syndrome; LAGB, laparoscopic adjustable gastric banding; MHFMD, Mild HFMD; ESHFMD, Extremely severe HFMD.

Expression levels of miR-671 can be used as diagnostic marker in placenta accreta spectrum, osteoarthritis and hand, foot, and mouth disease (Table 7). The best AUC values have been obtained in extremely severe cases of hand, foot, and mouth disease where mir-671 levels could differentiate this condition from healthy status with AUC value of 1.00 (Jia et al., 2014).

Diagnostic value of miR-671 in diseases (Mild HFMD: MHFMD, extremely severe HFMD: ESHFMD).

Disease type microRNA type Samples Distinguish between Area under curve Sensitivity (%) Specificity (%) References
Placenta accreta spectrum (PAS) miR-671-3p 12 PAS patients + 12 healthy pregnant women in the screening phase/41 PAS patients + 41 healthy pregnant women in the training phase/20 PAS patients+20 PP patients+20 PE patients and 20 healthy pregnant PAS vs. healthy pregnant women 0.70 57 76 Chi et al. (2020)
Osteoarthritis (OA) miR-671-3p 12 OA patients + 12 controls OA patients and healthy controls 0.87 - - Ntoumou et al. (2017)
Hand, foot, and mouth disease (HFMD) miR-671-5p 18 ESHFMD + 18 MHFMD + 18 healthy controls MHFMD vs. healthy controls 0.79 82 72 Jia et al. (2014)
ESHFMD vs. healthy controls 1.00 100 100 Jia et al. (2014)
ESHFMD vs. MHFMD 0.82 83 78 Jia et al. (2014)
Discussion

miR-671 is a miRNA with various roles in human disorders. In the context of cancer, different studies have revealed opposite roles for this miRNA. In brief, it has been shown to be down-regulated in pancreatic ductal carcinoma, ovarian cancer, gastric cancer, osteosarcoma, esophageal squamous cell carcinoma and myelodysplastic syndromes. Yet, miR-671 has been up-regulated in glioma, colorectal cancer, prostate cancer and hepatocellular carcinoma. Studies in breast, lung and renal cell carcinoma have reported inconsistent results which cannot be explained by the differences in the roles of miR-671-3p or miR-671-5p. It is possible that this miRNA exert stage- or grade-specific roles in the carcinogenesis.

miR-671 has functional interactions with circ_PTPRA, circ_0092314, circDLC1, circ_0001946, circSLC8A1, circRIP2, circ_0000620, circPIP5K1A and circCDR1as. In fact, these circRNAs act as molecular sponges for miR-671 to influence expression of miR-671 targets. NF-ƙB, EGFR, PTEN/PI3K/AKT, Wnt, HIF-1α, STAT3 and AKT/ERK/mTOR signaling pathways are among those being influenced by dysregulation of miR-671 in different cancers. Moreover, miR-671 has a role in the regulation of EMT in different tissues. This finding is based on functional studies on the role of this miRNA or circRNAs that sponge this miRNA. Thus, miR-671-targetin therapies might affect progression of cancer, invasiveness and metastatic ability of malignant cells.

miR-671 has also been suggested to predict course of cancers originated from different tissues. This speculation is based on the observed associations between dysregulation of this miRNA and survival of patients as well as correlation between its expression levels and clinicopathological data. However, the role of miR-671 as a diagnostic marker for cancers should be investigated in future. Based on the inconsistencies regarding the exact effects of miR-671 in the development and progression of different cancers, it is not expected that miR-671-targetted therapies enter the clinics in near future. More researches are needed to assign a definite role for this miRNA in each type of cancer.

The impact of miR-671 polymorphisms on risk of cancers has only assessed in sarcoma. Similar studies should be conducted to evaluate the association between these polymorphisms and risk of other cancers.

miR-671 has also a fundamental role in the pathophysiology of non-malignant conditions such as atherosclerosis, ischemic stroke, liver fibrosis, osteoarthritis, Parkinson’s disease, rheumatoid arthritis, acute myocardial infarction and Crohn’s disease. Moreover, it has a potential to be used as a diagnostic marker for placenta accreta spectrum, osteoarthritis and hand, foot, and mouth disease. However, dysregulation of miR-671 in malignant and non-malignant disorders originated from a certain tissue complicates the diagnostic application of this miRNA. Meanwhile, contribution of miR-671 to the pathogenesis of both malignant and non-malignant diseases is best explained by the prominent role of this miRNA in the regulation of activity of signaling pathways the control cell proliferation and apoptosis.

Taken together, miR-671 is a miRNA that can affect several target mRNAs and influence activity of signaling pathways that are involved in a variety of human disorders. However, several questions should be answered in order to propose miR-671-targeted therapies as efficient therapies for human disorders.

 Author contributions

SG-F wrote the draft and revised it. MT designed and supervised the study. AA, BH, and AK collected the data and designed the figures and tables. All the authors read the submitted version and approved it.

 Funding

This study was financially supported by Shahid Beheshti University of Medical Sciences.

The authors would like to thank the clinical research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their support, cooperation and assistance throughout the period of study.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

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