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Circular RNAs (circRNAs) play vital roles in the pathogenesis and development of multiple cancers, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory mechanisms of circ‐SPECC1 in HCC remain poorly understood. In our study, we found that circ‐SPECC1 was apparently downregulated in H2O2‐treated HCC cells. Additionally, knockdown of circ‐SPECC1 inhibited cell proliferation and promoted cell apoptosis of HCC cells under H2O2 treatment. Moreover, circ‐SPECC1 inhibited miR‐33a expression by direct interaction, and miR‐33a inhibitor partially reversed the effect of circ‐SPECC1 knockdown on proliferation and apoptosis of H2O2‐treated HCC cells. Furthermore, TGFβ2 was demonstrated to be a target gene of miR‐33a and TGFβ2 overexpression rescued the phenotypes of HCC cells attenuated by miR‐33a mimics. Meanwhile, autophagy inhibition by 3‐methyladenine (3‐MA) abrogated the effect of miR‐33a mimics on proliferation and apoptosis of H2O2‐treated HCC cells. Finally, knockdown of circ‐SPECC1 hindered tumor growth in vivo. In conclusion, our study demonstrated that circ‐SPECC1 regulated TGFβ2 and autophagy to promote HCC tumorigenesis under oxidative stress via miR‐33a. These findings might provide potential treatment strategies for patients with HCC., We confirmed the specific role and molecular mechanism of circ‐SPECC1 in HCC and discovered that circ‐SPECC1 modulated TGFβ2 and autophagy under oxidative stress by sponging miR‐33a to promote HCC tumorigenesis.

Hepatocellular carcinoma is the most common primary malignancy of the liver. The chemotherapeutic drug cisplatin is widely used for advanced liver cancer. However, the development of cisplatin resistance in cancer cells, which is related to the decreased cellular susceptibility to apoptosis, results in a major limitation of cisplatin-based chemotherapy. Recently, triggering necroptosis has been proposed to be a novel therapeutic strategy to eradicate apoptosis-resistant cancer cells. In this study, we provided evidence that cisplatin could induce cell death in HepG2 cells, but not in the apoptosis-resistant HepG2/DDP cells. Ectopic expression of RIP3 promoted cisplatin-induced HepG2/DDP cells death, HMGB1 and LDH release. Moreover, we demonstrated that this type of cell death was necroptosis and depended on RIP1-RIP3-MLKL signaling pathway because inhibition of MLKL activity by necrosulfonamide (NSA) or knockdown of RIP1 significantly attenuated cisplatin-induced cell death in HepG2/DDP-RIP3 cells. Finally, we found that ectopic expression of RIP3 sensitized HepG2/DDP cancer cells to cisplatin treatment in vivo. The findings offer new insights into the molecular mechanisms underlying cisplatin-induced necroptosis in liver cancer cells and suggest that combination of cisplatin with other drugs which can restore RIP3 expression in cancer cells maybe a better choice for therapy of apoptosis-resistant cancer.

The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC.