The subcellular localization of LINC00665 in BCa cells is well studied. Evidence based on fluorescence in situ hybridization (FISH) and subcellular fractionation followed by RT-qPCR showed that LINC00665 was mainly located in the cytoplasm (16, 17). LINC00665 is remarkably elevated in 106 BCa tissues and cell lines (MDA-MB-231 and MCF-7), and its expression is significantly associated with tumor size and TNM stage. LINC00665 knockdown suppresses BCa cell proliferation, migration, and invasion, but promotes cell apoptosis. Mechanically, LINC00665 silencing could inhibit β-catenin expression through competitively binding miR-3619-5p in BCa cells (18). Increasing evidence found that LINC00665 acted as a sponge for miR-379-5p (16) and miR-551b-5p (19) in BCa. Dai et al. (20) explored the correlation between LINC00665 expression and pathological complete response (pCR) in 102 neoadjuvant chemotherapy BCa patients. The results showed that LINC00665 expression was an independent predictor of pCR (OR = 0.351, 95% CI: 0.125–0.936, p = 0.040), especially in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative subtypes (OR = 0.272, 95% CI: 0.104–0.664, p = 0.005). Although LINC00665 has no protein-coding function, it was found to encode biologically active micropeptide. Guo et al. (17) revealed that LINC00665 was regulated by TGF-β at the translational level and encoded micropeptide CIP2A‐BP, thus participating in BCa progression. LINC00665 may promote BCa cell metastasis by triggering the epithelial–mesenchymal transition (EMT) process (21).

Xue et al. (22) observed that LINC00665 expression was upregulated in 50 PCa tissues and cell lines (LNCaP, 22RV1, PC-3,and DU-145) compared with corresponding control groups. Upregulated LINC00665 expression was correlated with the advanced T stage, lymph node metastasis, and the poor survival of PCa patients. Moreover, LINC00665 knockdown significantly suppressed PCa cell proliferation and migration. To further explore the biological mechanism of LINC00665, the subcellular fractionation assay found that LINC00665 was mainly located in the nucleus of PCa (22RV1 and DU-145 cells). Mechanically, LINC00665 may epigenetically inhibit KLF2 transcription and expression through recruiting EZH2 and LSD1 to its promoter region, thus playing an oncogenic role in PCa. LINC00665 could also promote PCa progression as a ceRNA through the miR-1224-5p/SND1 axis (23). Eke et al. (24) studied radiation-induced lncRNA dysregulation and found that LINC00665 was upregulated in LNCaP PCa cells at 2 months after a single dose of 10 Gy but not after multifractionated irradiation. Subsequent cell function assays showed that LINC00665 regulated the expression of the DNA repair proteins CtIP (RBBP8) and XPC.

Compared with adjacent normal tissues and a normal liver cell line HL-7702, LINC00665 was highly expressed in 76 HCC tissues and HCC cell lines (Huh-7, HepG2, HCCLM6, MHCC-97H, and Hep3B) (25). High LINC00665 expression was associated with the advanced tumor size, Edmondson grade, and the poor survival of HCC patients. In vitro and in vivo assays indicated that LINC00665 knockdown inhibited HCC cell viability and tumor growth, and induced apoptosis and autophagy. Further molecular regulatory investigation revealed that LINC00665 modulated the expression of MAP4K3 by sponging miR-186-5p. The findings of upregulated LINC00665 in HCC were also confirmed by Wen et al. (26) using TCGA, GEO, and quantitative real-time polymerase chain reaction (qRT-PCR) data. Ding et al. (27) performed an RNA-sequencing analysis in Huh-7 cells that were treated with TNFα, IL-1β, or INF-γ to identify the NF-κB-associated lncRNAs in HCC, and found that LINC00665 was the most highly induced upregulated lncRNA. In line with other studies, LINC00665 was upregulated in (84/122) HCC tissues and its expression was positively correlated with TNM stages, Barcelona Clinic Liver Cancer (BCLC) stages, and the poor prognosis of HCC patients. Furthermore, LINC00665 physically interacted with PKR and played an oncogenic role by promoting PKR activation and stability, thus giving feedback on prosperous NF-κB signaling in HCC.

Wu et al. (30) measured the expression level of LINC00665 in 67 pairs of CRC tissues and cell lines by qRT-PCR. The findings showed that LINC00665 was overexpressed in CRC tissues and cell lines, and LINC00665 knockdown suppressed CRC cell proliferation and promoted cell apoptosis. The subcellular distribution of LINC00665 in CRC cells was mainly in the cytoplasm. Mechanistically, LINC00665 could sponge miR-126-5p to regulate PAK2 and FZD3 expression. A study by Han et al. (31) also found that LINC00665 was abnormally upregulated in CRC cells and mainly located in the cytoplasm of HCT-116 and SW480 cells. Molecular investigations found that LINC00665 could increase the expression of CTNNB1 by sponging miR-214-3p or binding to U2AF2 protein, further activating the Wnt/β-catenin signaling pathway to promote the tumorigenesis of CRC. In addition, upregulated LINC00665 stimulated CRC progression by regulating the miR-9-5p/ATF1 axis (32).

In the digestive tract, GC remains a common malignant tumor with a high incidence and mortality and a poor prognosis (62). LINC00665 was first identified to be overexpressed in 49 paired GC tissues and cell lines in a study by Qi et al. (33). High LINC00665 expression was also found to be associated with an advanced TNM stage and the histological grade of GC. Moreover, in vitro assays showed that LINC00665 may promote the proliferation and invasion of GC cells, and as a ceRNA for miR-149-3p to regulate the expression of RNF2. Yang et al. (34) demonstrated that LINC00665 silencing could significantly inhibit GC cell proliferation, migration, invasion, and induce apoptosis in vitro, as well as restrain tumor growth in vivo. The Wnt pathway, also named Wnt/β-catenin, was known to play a crucial role in GC tumorigenesis and was found to be activated by LINC00665. In addition, LINC00665 could facilitate the proliferation, invasion, and metastasis of GC cells via activating the TGF-β signal pathway (35). Acquired resistance to cisplatin (DDP)-based chemotherapy is a common clinical issue in the treatment of GC. Yue et al. (36) reported that LINC00665 expression was higher in DDP-resistant GC cell lines than that in normal gastric mucosal epithelial cell lines and DDP-sensitive GC cell lines. LINC00665 knockdown inhibited DDP-resistant GC cell proliferation, induced apoptosis, and improved its DDP sensitivity by suppressing endoplasmic reticulum (ER) stress.

According to the pathological pattern, lung cancer cases are divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for approximately 85% and its primary subtype is lung adenocarcinoma. Yang et al. (39) found that LINC00665 was upregulated in lung cancer tissues by analyzing the TCGA database, and further qRT-PCR assay confirmed that it was highly expressed in 51 of 60 NSCLC tissues. High LINC00665 expression was associated with advanced tumor size, TNM stage, and lymph node metastasis. Kaplan–Meier survival analysis indicated that patients with high LINC00665 expression had poorer overall survival (OS) and progression-free survival than those with low expression. Functionally, LINC00665 knockdown suppressed NSCLC cell proliferation and migration and promoted cell apoptosis. Further assays in vitro and in vivo showed that LINC00665 knockdown improved the sensitivity of NSCLC cells to DDP. Based on the findings that LINC00665 was primarily distributed in the cytoplasm of NSCLC cells, LINC00665 was found to recruit EZH2 to the CDKN1C promoter region to facilitate the demethylation of histone H3K27 and inhibit CDKN1C transcription. As a ceRNA, LINC00665 could regulate the expression of E2F3, AKR1B10, ZIC2, MYCBP, and CCNA2 by sponging miR-138-5p (40), miR-98 (41), miR-181c-5p (42), miR-195-5p (43), and miR-let-7b (44), respectively. LINC00665 also participated in tumor angiogenesis. Cong et al. (45) uncovered that YB-1 protein stability was improved by directly interacting with LINC00665, and thus activated the transcription and expression of ANGPT4, ANGPTL3, and VEGFA by binding to their promoters in the process of tumor angiogenesis. A recent study also found that LINC00665 was overexpressed in lung cancer tissues and cells with acquired gefitinib resistance (46). A series of assays in vitro and in vivo confirmed that LINC00665 promoted the resistance of NSCLC cells to gefitinib by increasing EZH2 and activating the PI3K/AKT pathway.

OC, with high mortality and poor prognosis, is one of the most common malignant tumors in the female reproductive system. Gao et al. (50) found that LINC00665 was upregulated in OC tissues by analyzing the GEPIA database and constructing a prognosis correlated with the LINC00665-miR-146a-5p-CXCR4 regulatory network. LINC00665 expression was positively correlated with infiltrating levels of CD4+ T cells and negatively correlated with CD8+ T cells, neutrophils, macrophages, and dendritic cells, which demonstrated the correlation between LINC00665 and lymphocyte infiltration in high-grade serous OC (51). Moreover, a nine-autophagy-related lncRNA signature (including LINC00665) was constructed as independent prognostic factors for the OS of OC patients (52). LINC00665 may regulate E2F3 expression through competitively binding to miRNA-34a-5p in promoting OC progression (53).

Through lncRNA microarray analysis, LINC00665 was identified to be differentially expressed in glioma. Further RT-qPCR assays confirmed the high expression levels of LINC00665 in 48 glioma tissues and cell lines. Based on the evidence that LINC00665 was mainly distributed in the cytoplasm, Dai et al. discovered that the LINC00665/miR-34a-5p/AGTR1 axis contributed to the development and progression of glioma (37). In addition to the ceRNA regulatory pathway, lncRNAs, which were located in the cytoplasm, could regulate mRNA expression through STAU1-mediated mRNA degradation (63). Ruan et al. (38) reported that LINC00665 was downregulated in glioma tissues and cells and acted as a tumor suppressor gene. Further exploration found that LINC00665 facilitated the degradation of MTF1 and YY2 mRNA via interacting with a double-stranded RNA-binding protein STAU1. The Alu elements on LINC00665 and MTF1 or YY2 mRNA 3’UTR constructed a STAU1-binding site through complementary base pairing; thus, STAU1 executed mRNA decay via binding to the constructed site.

LINC00665 expression was upregulated in 42 osteosarcoma tissues and four cell lines. Further clinicopathological correlation analysis indicated that higher LINC00665 expression was correlated with larger tumor size, later clinical stages, and poorer OS. Mechanistically, LINC00665 facilitated osteosarcoma progression by increasing RAP1B expression via targeting miR-708 and miR-142-5p (28). LINC00665 could also promote osteosarcoma progression by sponging miR-3619 (29). Compared with normal human epidermal melanocytes, LINC00665 expression was significantly increased in four melanoma cells lines (A375, M21, A2058, and A-875). A series of assays in vitro and in vivo showed that LINC00665 was mainly expressed in the cytoplasm and could promote the malignant behaviors of melanoma cells through the miR-224-5p/VMA21 axis (47). Xia et al. (56) demonstrated that LINC00665 may promote HeLa cell proliferation, metastasis, and EMT via the WNT-CTNNB1/β−catenin signaling pathway. In endometrial carcinoma, LINC00665 was overexpressed in endometrial carcinoma tissues and cell lines. Mechanistically, LINC00665 co-immunoprecipitated with the HMGA1 protein and promoted the tumorigenicity of endometrial carcinoma in vitro and in vivo (48). Lu et al. (49) explored the role of LINC00665 in gemcitabine resistance of cholangiocarcinoma and found that LINC00665 was upregulated in gemcitabine-resistant cells. High LINC00665 expression was positively correlated to advanced TNM stage, lymph node/distant metastasis, and poor prognosis. Assays in vitro and in vivo indicated that LINC00665 increased the gemcitabine tolerance of cholangiocarcinoma cells by regulating EMT, stemless properties, and the miR-424-5p/BCL9L axis. Through extracting the RNAs from acute myeloid leukemia (AML) or normal bone marrow tissues and cells, an RT-qPCR assay displayed that LINC00665 was upregulated in AML tissues and cell lines. LINC00665 could accelerate the progression of AML by regulating the miR-4458/DOCK1 axis (54). LINC00665 was also found to be upregulated in T-cell acute lymphoblastic leukemia (T-ALL) and could promote T-ALL progression through the miR-101/PI3K/Akt pathway (55).