Among female reproductive system tumors, ovarian cancer is the most common, and it is one of the most aggressive (1). Ovarian cancer is usually diagnosed at an advanced stage with a poor prognosis due to the absence of clinical symptoms in the early stages and the high failure rate of chemotherapy (2). It is estimated that in 2020, there will be around 3,13,959 new cases of ovarian cancer globally, with an incidence of 6.6 and a mortality rate of 4.4, according to the data survey (3). In spite of improvements in survival rates for women with ovarian cancer in the past few decades, the 5-year survival rate for women with stage I epithelial ovarian cancer remains below 30%. It is well known that the miR-34 family (miR-34s) is essential for the pathogenesis of epithelial ovarian cancer, and its inactivation might have significant implications for its progression (2). Therefore, in order to improve the prognosis of ovarian cancer patients, biomarkers relating to prognosis must be identified and new therapeutic targets explored.

There are approximately 22 nucleotides in the length of microRNA (miRNA; miR) that are endogenous non-coding RNA. The miRNA negatively regulates gene expression at the post-transcriptional and translational levels, and plays a significant role in cancer progression (4). miR-34s is a family of three miRNAs that is encoded by two different genes in the human body, miR-34a, miR-34b, and miR-34c. There is an individual transcript for miR-34a on chromosome 1p36.22; however, miR-34b and miR-34c share the same chromosome 11q23.1 for transcription and expression (5). Several processes in tumor development are regulated by the tumor suppressor miR-34s, which is low expressed in most tumors, including proliferation, migration, invasion, metabolism, apoptosis, and cancer stem-cell formation, cell cycle progression, epithelial mesenchymal transformation, and so on, the result is an inhibition of tumor growth and metastasis (2, 6). Direct transcriptional targets of p53 have been shown to be miR-34a and miR-34b/c (7). According to Hannah Welponer et al. (8)show that The levels of miR-34a/b/c in ovarian cancer were found to be significantly decreased compared to control tissues (p=0.002, p<0.001, p<0.001, respectively). Furthermore, the expression of each member of the miR-34 family was determined to have independent prognostic significance in relation to progression-free survival (PFS) (miR-34a: HR=0.6, p=0.033; miR-34b: HR=0.2, p=0.001; miR-34c: HR=0.3, p=0.002, respectively). It was determined that miR-34b (HR=0.4, p=0.016) and miR-34c (HR=0.6, p=0.049) have a prognostic value for overall survival (OS). Research conducted by Jia et al. (9) found no correlation between the presence of miR-34a and overall survival (HR=1.407, p=0.929) or progression-free survival (HR=0.855, p=0.727) in individuals with epithelial ovarian cancer. However, a study by Song et al. (10) found significant effects of tumor size, FIGO stage, histological type, and miR-34c expression on overall survival in ovarian cancer patients. An analysis of multivariate data found a significant association between miR-34c expression and shorter OS time (p=0.038). Consequently, it is necessary to evaluate miR-34s expression and ovarian cancer survival through meta-analysis in order to determine the diagnosis and prognosis assessment of the miR-34s.

In this study, in order to obtain more accurate information about the prognosis of ovarian cancer, miR-34s expression needs to be further studied. Reviewing relevant literature and using systematic reviews and meta-analyses to assess miR-34s prognostic value in ovarian cancer was the goal of this study.

Researchers have examined the relationship between miR-34s expression and survival in ovarian cancer patients. A total of 87 literatures were collected through six database and other ways, and 7 literatures were finally included. Firstly, a NOS quality assessment was conducted on the seven included studies, which were generally deemed to be of high quality. A pooled analysis of nine studies with 672 women, higher expression of miR-34s significantly increased OS and PFS for patients with ovarian cancer. Based on the significant heterogeneity of the outcome indicator PFS, stratified analysis by miR-34s member types identified miR-34a and miR-34c expression levels are higher as significantly associated with increased PFS. Lastly, sensitivity analysis found that no single study had a significant impact on overall results, and that the results were relatively stable and reliable. Using a publication bias test, the funnel plot was found to be roughly symmetrical, without evidence of publication bias.

The meta-analysis of research studies revealed that miR-34s expression was associated with a significant improvement in ovarian cancer patients’ OS and PFS. These findings align with the results reported by Schmid et al. (15), indicating that ovarian cancer cases with reduced miR-34a expression exhibited a decrease in PFS (p = 0.039) and OS (p = 0.016). Researchers have found that miR-34s expression levels are lower in cancerous tissues than non-tumorous tissues in ovarian cancer tissues (8). Ovarian cancer exhibiting elevated miR-34a and miR-34c levels may demonstrate reduced malignant potential, decreased invasiveness, and limited dissemination (8). Kwan et al. (17) observed there is a notable decrease in miR-34s expression in a number of malignant tumors, including breast cancer and colon cancer. They further demonstrated that this downregulation facilitated tumor suppression by modulating key molecular pathways involved in tumorigenesis. Inhibition of lung squamous cell carcinoma proliferation, migration, and invasion was associated with high miR-34s expression, according to Sun et al. (18) By targeting miR-34c, Wang et al. (19) demonstrated in vivo and in vitro that miR-34c inhibited malignant behaviors such as invasion, migration, proliferation, and epithelial-mesenchymal transformation of nasopharyngeal carcinoma. According to Elena et al. (20), it is possible that miR-34a can serve as an important indicator of recurrence in patients with non-small cell lung cancer. The diminished expression of miR-34s in osteosarcoma and hepatoblastoma has been correlated with an unfavorable prognosis (21, 22). Hence, it is believed that reduced miR-34s expression is a crucial factor in the initiation and progression of tumor growth.

We acknowledge that the heterogeneity for PFS in our study was high (I² = 72%), indicating significant differences among the included studies. To explore potential sources of this heterogeneity in more detail, we conducted a subgroup analysis to evaluate the impact of different RNA families on the results. Subsequently, we found that after performing the subgroup analysis, the I² value decreased to below 50%, suggesting that these subgroupings explain a substantial part of the heterogeneity. miR-34s represent the initial miRNA identified as being directly regulated by p53, with miR-34a demonstrating the most pronounced level of regulation by p53 (23). Furthermore, p53 and miR-34a expression is influenced by various indirect regulatory factors; for instance, miR-34a can enhance p53 activity by downregulating the expression of SIRT1, a NAD-dependent deacetylase involved in information regulation. Following the inhibition of p53 protein transcription, there is a subsequent down-regulation of p53 protein activity during the process of deacetylation (5, 24). In the context of epithelial-mesenchymal transition (EMT), miR-34 plays a crucial role by regulating the transcription factor Snail, which is pivotal in promoting EMT and invasion (16, 25). Additionally, miR-34a has been shown to negatively regulate E2F3a, a key transcription factor that promotes cell proliferation and facilitates the G1/S transition. In ovarian cancer cells, knockdown of miR-34a resulted in a significant increase in E2F3 expression, highlighting its role in cell cycle regulation (14). Moreover, miR-34a’s role extends to apoptosis, where its expression can influence apoptotic pathways, promoting cell death in cancer cells. This suggests that miR-34a not only acts as a tumor suppressor through cell cycle arrest and EMT regulation but also enhances apoptosis, thereby contributing to the suppression of malignant characteristics in ovarian cancer. For example, upregulation of miR-34a-5p has been shown to suppress the malignant characteristics of ovarian cancer cells by targeting TRIM44, impeding the advancement of the disease (26).Additionally, the miR-34 family members exhibit co-targeting of MET, a receptor protein tyrosine kinase, which influences the motility and invasion of epithelial ovarian cancer (27).Research has identified that MET is a target of miR-34c, enhancing the anti-tumor efficacy of cisplatin in ovarian cancer cells (28).In a study by Lu et al. (29), reverse transcriptional quantitative PCR demonstrated a significant reduction in exosome miR-34b expression in ovarian cancer cells, suggesting that exosome-derived miR-34b can diminish cell proliferation and hinder EMT in the SKOV3 ovarian cancer cell line. Based on these mechanistic studies, the findings collectively emphasize the importance of miR-34s in the cellular biology of ovarian cancer, particularly regarding their suppressive impact on proliferation, invasion, and promotion of apoptosis.

According to Kumar et al. (3), a MeDIP-NGS analysis revealed significant decreases in the relative expression levels of microRNA-34a in both tissue and serum samples of early epithelial ovarian cancer (p<0.0001). Furthermore, the functional analysis of microRNA-34a demonstrated that patients with stage III-IV and I-II epithelial ovarian cancer (EOC) had areas under curves of 92.0 (p<0.0001) and 82.7 (p<0.0001), respectively, suggesting that serum samples from these patients may be useful for monitoring cancer progression. In summary, miR-34s may serve as potential biomarkers in the diagnosis and prognosis of ovarian cancer. However, limitations such as varying sample sources, a paucity of literature, and inadequate sample sizes within studies may compromise the statistical robustness of miR-34s’ prognostic value. By controlling for certain objective conditions, it is feasible to accurately forecast the prognosis of miR-34s expression in ovarian cancer.

Based on the results of this review, miR-34s could potentially serve as a prognostic indicator for an improved survival outcome for female ovarian cancer patients. However, due to the constraints of the present analysis, it is advisable to exercise caution when interpreting the conclusions. Additional clinical trials with rigorous methodology, a substantial sample size, and an extended follow-up period are necessary to further elucidate the prognostic significance of miR-34s expression in ovarian cancer.