High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.

Radiotherapy and adjuvant cisplatin (DDP) chemotherapy are standard approaches used in the treatment of nasopharyngeal carcinoma (NPC). However, resistance to chemotherapy has recently become more common, resulting in the failure of this combination therapy for NPC. The aim of the present study was to assess the cellular morphology, motility and molecular changes in DDP-resistant NPC cells in relation to epithelial-mesenchymal transition (EMT). CNE2 cells were continuously exposed to increasing doses of DDP to establish a stable cell line resistant to DDP (CNE2/DDP cells). The human NPC cell lines, HNE1, CNE2, HNE1/DDP and CNE2/DDP, were used to examine the association between chemoresistance and the acquisition of an EMT-like phenotype of cancer cells. The DDP-resistant cells were less sensitive than the HNE1 cells to treatment with DDP, and were shown by a cell viability assay, western blot analysis and qRT-PCR to have acquired chemoresistance. The HNE1/DDP cells examined by wound healing and Transwell Boyden chamber assays exhibited an increased migration and invasion potential. The DDP-resistant cells exhibited morphological and molecular changes consistent with EMT, as observed by western blot analysis and qRT-PCR. These changes included becoming more spindle-like in shape, a loss of polarity and formation of pseudopodia, the downregulation of E-cadherin and β-catenin and the upregulation of vimentin, fibronectin and matrix metalloproteinase (MMP)-9. Moreover, the levels of the EMT-related transcription factors, Snail, Slug, Twist and zinc finger E-box binding homeobox 1 (ZEB1), were higher in the DDP‑resistant NPC cells. These data suggest that the development of DDP resistance of NPC cells is accompanied by inducible EMT-like changes with an increased metastatic potential in vitro. Further elucidation of the association between resistance to DDP and EMT may facilitate the future development of novel therapeutic approaches for the treatment of chemoresistant tumors.

No abstract

Tumor metastasis is the ultimate stage of cancer, and the primary cause of mortality in patients. Tumor cells breaking through the natural barrier consisting of the basement membrane (BM) and extracellular matrix (ECM) is the a crucial step in tumor invasion and metastasis. Thus, protecting this barrier is the key to reducing mortality. Heparanase is a mammalian endo-β-glucuronidase which has been found to promote the cleavage of heparan sulfate (HS), and plays a significant role in tumor cell invasion and metastasis. Although chemotherapeutic reagents have a strong antitumor activity, they may promote the invasion and migration of cancer cells, as has been observed during clinical treatment. Chemotherapeutic reagents can induce endoplasmic reticulum (ER) stress; in this study, we used adriamycin (ADM) and a classical ER stress inducer, tunicamycin (TM). We report that the activation of ER stress is involved in the enhanced invasion and migration ability of breast cancer cells and we hypothesized that this effect is associated with the activation of heparanase. In support of this, we used the heparanase inhibitor, OGT2115, and low molecular weight heparin (LMWH) to inhibit the expression and activity of heparanase, and we found that the invasion and migration ability of the cells was suppressed. Our findings demonstrate that heparanase inhibitors suppress breast cancer cell invasion and migration induced by ER stress, and provide a strong rationale for the development of heparanase-based therapeutics for the prevention of metastasis induced by chemotherapeutic reagents.

Temozolomide (TMZ) resistance is the main challenge in the management of glioma patients. Heparanase can mediate the secretion and function of exosomes, which are considered to be a promising molecular delivery system for cancer therapy. Therefore, this study aimed to investigate whether heparanase‐mediated delivery of exosomes was related to TMZ resistance of glioma. Heparanase was upregulated in TMZ‐resistant glioma cells, and overexpression of heparanase led to increased resistance of U87 cells to TMZ. Knockdown of heparanase led to increased sensitivity of TMZ‐resistant U251 cells (U251R) cells to TMZ. Heparanase promoted the secretion of exosomes from glioma cells, and coculture with exosomes derived from heparanase knockdown U251R cells partly restored the sensitivity of U251 cells to TMZ compared with exosomes derived from si‐control transfected U251R cells. It was identified by circular RNA microarrays that hsa_circ_0042003 was upregulated in exosomes derived from U251R, which could be positively regulated by heparanase. U251R cell‐derived exosomal hsa_circ_0042003 conferred the resistance of U251 cells to TMZ. In vivo studies also showed that U251R cell‐derived exosomes induced resistance of U251 cells to TMZ, and the combination of tail‐injected exosomal si‐heparanase or exosomal si‐hsa_circ_0042003 and intraperitoneal TMZ applied to nude mice abolished TMZ resistance. Heparanase mediated the transfer of exosomal hsa_circ_0042003 from TMZ‐resistant glioma cells to drug‐sensitive cells, which contributed to the chemoresistance of glioma to TMZ.