Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Abstract

Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominantnegative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3′-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR199a, and HIF, with implications in cancer metastasis.microRNA | iron regulation E pithelial ovarian cancer (EOC) is the leading cause of death among the gynecological malignancies (1). Ascites development and peritoneal metastasis are unique features of ovarian cancer progression. Gas analyses of ovarian cancer ascites show about 2.5% dissolved oxygen content, whereas the blood oxygen content ranges between 15% and 23% (2). Hypoxic areas are common in tumor microenvironment as increased metabolic demands of rapidly proliferating cells outpace oxygen availability. Sustained exposure to hypoxia spurs cells to reorganize cellular processes, and energy-consuming functions, such as endocytosis, are suppressed (3, 4). Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (HIF-1α/HIF-2α) are principal coordinators of these responses. HIF-1α/HIF-2α are stabilized in hypoxia and associate with hypoxia-inducible factor-1β (HIF-1β) to form heterodimeric transcription factors and induce the expression of target genes (5, 6). HIF-1-mediated expression of lysyloxidase (LOX) cross-links collagens and induces cell migration (7). Epithelial ovarian cancer cells (EOCCs) that have adapted to hypoxia by activating HIF-1 disseminate from primary ovarian tumors and exfoliate into the peritoneal cavity. HIF-1 significantly enhances gene signatures associated with tissue remodeling, the morbidity and mortality associated with EOC (8, 9).Regulation of HIF-1 is a key step in the hypoxic response with profound implications for EOC metastasis. Under normoxia, HIF-1α is hydroxylated within its oxygen-dependent degradation domain (ODDD) by prolylhydroxylases (PHDs). This reaction is an oxygen-, iron-, 2-oxoglutarate and ascorbate-dependent process. Hydroxylated HIF-1α is recognized and bound by a complex that...

miR-199a-5p regulates HIF-1α and OSGIN2 and its expression is correlated to soft-tissue sarcoma patients' outcome

“…Several studies have described miR-199a as a type of miRNA associated with hypoxia-adaptation (36)(37)(38)(39). It was demonstrated that miR-199a-5p downregulation is AKT-dependent (39,40) and may be antagonized by the β-adrenergic receptor (40).…”

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

“…In vivo, miR-199 inhibits growth and peritoneal seeding of ovarian tumors after i.p. injection of SKOV3 and A2780 cells (70,71). In these models total tumor burden and number of metastases on the peritoneal surface, omentum, small bowel mesentery and both ovaries were reduced.…”

“…miR-199 is down-regulated in the majority of EOCs and has been shown to directly target pro-metastatic proteins such as c-MET, HIF-1α, HIF-2β and Iĸ kinase β IKKβ in this tumor entity (Figure 3) (70-72). In EOC cell lines, miR199 inhibits proliferation, invasion and adhesion as well as extracellular signal regulated kinase and nuclear factor ĸB (NFĸB) signaling (70)(71)(72). Inhibition of HIF levels, down-regulates lysyl-oxidase (LOX), a matrix remodeling enzyme which cross-links collagens (73).…”

Non-Coding RNAs Mediate Chemotherapy Resistance in Ovarian Cancer

“…High ALDH1 expression was associated with chemoresistance in in vitro and ex vivo samples [26]. Besides, miR-200 family [27][28][29][30], miR-199/214 cluster [31][32][33][34][35], miR-31 [36] et al, are also reported to be connected with chemotherapy resistance, including cisplatin and pactitaxel (Table 1). [25] miR-591 ZEB1 Paclitaxel resistance [25] miR-23b ALDH1 Chemoresistance [26] miR-27a ALDH1 Chemoresistance [26] miR-27b ALDH1 Chemoresistance [26] miR-346 ALDH1 Chemoresistance [26] miR-424 ALDH1 Chemoresistance [26] miR-503 ALDH1 Chemoresistance [26] miR-200 family…”

“…IKKβ, HIF-1A, HIF-2A CD44 JAG1 PTEN, CCL5 Chemosensitivity Chemosensitivity Cisplatin sensitivity Cisplatin resistance [32,33] [31]…”