Previous evidence indicates that the dysregulation of miRNAs might play an essential role in the pathogenesis of ovarian cancer. Besides, circulating miRNAs in serum have emerged as potential biomarkers for detecting various diseases, including cancer. The study results revealed that the expression of miRNA-34a, miRNA-143, miRNA-212 significantly altered in serum of patients compared to healthy subjects.
The results of our study showed that the expression level of circulating miRNA-34a decreased in the patient compared to the control group. Besides, the result of our investigation showed that miRNA-34a could serve as a promising biomarker for the diagnosis of ovarian cancer. MiR34 family members are well known to manage the cell cycle, apoptosis, and invasiveness in cancer (Gou, Dai et al. 2014, Li, Liu et al. 2014)(Li et al., 2014). These miRNAs are verified to have a straight duty in the growth of breast, prostate, bladder, or brain cancer, and miR34a is taken into consideration to be an appealing therapeutic target in cancer therapy (Gou, Dai et al. 2014, Li, Liu et al. 2014)(Li et al., 2014). Besides, the study by Jin et al. has shown that decreased expression of miRNA-34a is associated with a poor prognosis of gallbladder cancer. They indicated that miRNA-34 acts as a tumour suppressor, and overexpression of it resulted in reduced xenograft tumours (Jin, Xiang et al. 2014). In addition, a Raised level of circulating miR34a and miR34b was reported in breast, lung, and prostate cancer (Lodes, Caraballo et al. 2009, Roth, Rack et al. 2010)(Lodes et al., 2009; Roth et al., 2010, 2011). However, restricted info is offered regarding circulating miR34 family members in ovarian cancer, and more in-depth investigation is needed to clarify the exact role of mir34 in ovarian cancer.
Also, the results of our study showed that the level of expression miRNA-143 in patients significantly decreased. Also, Previous reports showed that transfection of HeLa cells with pre-miRNA-143 could significantly decrease their proliferation and increase apoptosis. Also, they found that expression of miRNA-143 was decreased in cancerous cervical tissues compared to non-tumour tissues(Liu, Yu et al. 2012) . Wang et al. also showed that the expression of miRNA-143 was down-regulated in colon cancer but not in rectal cancer(Wang, Zhou et al. 2009) . So that miRNA-143 might be acting as a tumour suppressor, but more investigation is needed to clarify the role of this miRNA in the inhibition of ovarian cancer. In addition, our results showed that it could be an excellent marker for the early diagnosis of ovarian cancer along with miRNA-34a, but to our knowledge, it is the first time to analysis in ovarian cancer and needed more investigations.
Along with miRNA-34a and miRNA-143, we analysed the level of miRNA-212 in ovarian patients and healthy controls. The results showed that along with other miRNAs, it also could predict ovarian cancer. Besides, the literature review showed that the miRNA-212 in different malignancies could change differently. For instance, Incoronato et al. revealed that the miRNA-212 expression decreased in vivo and in vitro in lung cancer. Also, Wei et al. found that the expression of miRNA-212 was significantly down-regulated in both tissue and serum of epithelial ovarian cancer patients(Kenny and Bali 2013). Their results have revealed that overexpression of miRNA-212 in ovarian cancer cells could inhibit cell proliferation, migration, and invasion. In our study, the miRNA-212 level significantly decreased, and it might show possibilities that miRNA-212 can act as a tumour suppressor and a promising biomarker for the detection of ovarian cancer. In addition, the decreasing of miRNA-212 was along with increased expression of SOX4.
The previous investigation showed that miRNA-212 acts as a tumour suppressor in colorectal carcinoma by targeting SOX4(Mou, Zhang et al. 2019) . SOX4 is a vital developmental transcription factor in invertebrates and is essential for accurate differentiation and proliferation in various tissues. Furthermore, SOX4 is overexpressed in many human malignancies; however, the exact role of SOX4 in cancer progression is not well understood. Besides, SOX4 has been reported to be overexpressed in renal cell carcinoma, which promoted cell migration and invasion inducing EMT. In addition, SOX4 has been discovered to participate in metastasis and EMT in renal cell carcinoma, lung adenocarcinoma, and non-small cell lung cancer(Ruan, Yang et al. 2017, Tong, Meng et al. 2017) [29, 45]. Another experiment revealed that the Aryl hydrocarbon receptor-microRNA-212/132 axis in human breast cancer suppresses metastasis by targeting SOX4(Hanieh 2015). In addition, Dysregulation of the SOX4 correlates with the outcome of colorectal cancer (Andersen, Christensen et al. 2009).
Besides, our results showed that the level of E2F5 was significantly higher than the control group. E2F5 is an essential member of cell growth and proliferation by regulating the genes involved in cell cycle progression(Ren, Cam et al. 2002, Chen, Tsai et al. 2009) [27, 37]. In addition, it has been shown that some miRNA can inhibit cancer development via repressing E2F5 (Ren, Cam et al. 2002). Also, one investigation revealed that knockdown of E2F5 induces cell death via the TP53‑dependent pathway in breast cancer cells carrying wild‑type TP53 (Inagaki, Wu et al. 2020).
Also, the results showed that in cancer patients, the BCL-2 expression was higher than in the control group. Bcl-2-family proteins regulate all significant types of cell death, including apoptosis, necrosis, and autophagy, thus operating as nodal points at the convergence of multiple pathways with broad relevance to oncology(Chipuk, Moldoveanu et al. 2010) . Also, therapies targeting Bcl-2-family are currently in clinical testing, raising hopes that a new class of anticancer drugs may soon be available.
In conclusion, our data showed that the expression profile of miRNA-34a, miRNA-143, and miRNA-212 could act as a potential biomarker for diagnosing ovarian cancer patients. In addition, miRNA-34a, miRNA-143 circulating levels significantly decreased in patients and could serve as a tumour suppressor, but more investigation is needed to further show different targets to light on their role in the pathogenesis of ovarian cancer.