MicroRNA‐138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF‐1α

Abstract

Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low-and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1a (HIF-1a), and overexpression of SOX4 and HIF-1a effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1a by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138 low / SOX high signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1a pathways.Metastatic ovarian cancer is the deadliest among gynecologic malignancies, with an estimated 15,500 deaths in the United States in 2012, as reported by the National Cancer Institute. The overall 5-year survival rate is 33% when diagnosed at advanced stages; it is about 90% while the cancer is still confined to the ovary (stage I). 1 At late stages, tumor cells spread beyond the pelvic cavity and commonly undergo metastasis to the mesentery, omentum and diaphragm. 2 Metastasis to the pelvic and para-aortic lymph nodes may also occur. Elucidating the mechanisms underlying cancer metastasis will, thus, make significant contributions toward combating this disease. MicroRNAs (miRNAs), a family of small noncoding single-stranded RNAs, have recently been shown to play essential roles in cancer cell invasion and metastasis. 3 One miRNA can suppress multiple gene expressions by interacting with the 3 0 nontranslated regions (3 0 UTRs) of its target mRNAs and promoting their degradation or translational suppression resulting in the modulation of those genes' expressions and functions.A couple of recent studies have reported the role of miRNAs in modulating ovarian cancer cell invasion and metastasis. Cowden Dahl et al. showed that epidermal growth factor receptor (EGFR)-responsive miR-125a induced a mesenchymalto-epithelial transition (MET) in ovarian cancer cells. MiR125a directly targets ARID3B, which is overexpressed in serous ovarian cancer. 4 Corney et al. reported that p53-transactivated miR-34 was decreased in metastatic ovarian cance...

MicroRNA‑138 targets SP1 to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells

“…Yang et al (26) found that miR-138 expression resulted in a significant inhibition of colorectal cancer cell migration and invasion in vitro and in vivo. In ovarian cancer, miR-138 overexpression repressed cancer cell invasion and metastasis (24). In nasopharyngeal carcinoma, miR-138 markedly decreased cell proliferation and colony formation in vitro, and tumorigenesis in vivo (37).…”

MiR‐138 inhibits cell proliferation and reverses epithelial‐mesenchymal transition in non‐small cell lung cancer cells by targeting GIT1 and SEMA4C

“…MicroRNA is a kind of endogenous small non‐coding RNAs that could participate in many biological processes, including cell proliferation, apoptosis, cell differentiation and development 9, 16, 17, 25. It is believed that the dysregulation of miRNAs is closely related to the development and progression of a number of cancers 4, 5, 12, 13, 21.…”

“…MicroRNAs have been reported to regulate different properties of cancers, such as cancer cell proliferation, migration, invasiveness, EMT, and so on, by repressing their target gene expression 5, 8, 16, 17, 18. Recent evidences indicate that several miRNAs have been involved in the tumorigenic driver pathways in NSCLC, which would be developed as a new therapeutic strategy of NSCLC 2, 15.…”

Circular RNA participates in the carcinogenesis and the malignant behavior of cancer

“…Suppressing miR-138 aggravates the metastasis of ovarian cancer via activation of the LIM kinase 1 (Limk1)/cofilin signaling pathway. [66][67][68] By targeting histone family 2A variant, member X (H2AX), miR-138 is essential to regulate the DNA damage response in small cell lung cancer (SCLC) cells, the upregulation of which is responsible for the increased radiosensitivity of lung cancer. 69,70 MiR-138 plays roles not only in solid tumors, but also in chronic lymphocytic leukemia (CLL).…”