Exosomes derived from HBV-associated liver cancer promote chemoresistance by upregulating chaperone-mediated autophagy.

Liver cancer, which is the second leading cause of tumor-associated mortality, is of great concern worldwide due to its resistance to chemotherapeutic drugs. Transcatheter arterial chemoembolization (TACE) has previously been used as a treatment for unresectable liver tumors in China; however, the response to TACE treatment differs between patients. It has been reported that hepatitis B virus (HBV)-as sociated tumors are less sensitive to TACE treatment compared with non-HBV-associated liver cancer. Previous studies have demonstrated that exosomes serve a crucial role in hepatic carcinoma chemoresistance. We therefore hypothesized that HBV may modulate chemosensitivity via exosomes. The aim of the present study was to investigate how exosomes affect chemoresistance by assessing their role in chaperone-mediated autophagy (CMA)-dependent chemoresistance in HBV-associated liver cancer. Iconography data from HBV-positive and HBV-negative patients with hepatic carcinoma receiving TACE treatment were assessed, and it was revealed that the tumor volume was decreased in the patients with non-HBV-associated liver cancer compared with that in the patients with HBV-associated tumors following TACE therapy. Furthermore, it was revealed that exosomes from HBV-infected liver cancer cells were able to downregulate cell apoptosis when treated with oxaliplatin compared with exosomes from normal HepG2 cells. Furthermore, the results demonstrated that HBV-associated exosomes modulate cell death via activating the CMA pathway, and its key molecule, lysosome-associated membrane protein (Lamp2a), was also upregulated. Lamp2a-knockdown was also found to reverse anti-apoptotic effects in liver cancer. Taken together, the results of the present study suggest that chemoresistance in patients with HBV-associated hepatic tumors may be mediated by exosomes, and thus may provide a basis for the development of novel treatment strategies for chemoresistant liver cancer.

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway.

The interleukin (IL)-17/IL-17 receptor (IL-17R) complex has been shown to be important for the regulation of inflammation; however, its role in the regulation of tumor processes has recently emerged as a research focus. The present study demonstrated that oxaliplatin was able to increase the levels of IL-17/IL-17R in hepatocellular carcinoma (HCC) patients and cells lines, and that it had important roles in reducing the susceptibility of the cells to oxaliplatin-induced apoptosis. Furthermore, the expression of autophagy-related proteins was induced by IL-17/IL-17R and autophagy was shown to induce resistance to oxaliplatin in HCC. In addition, the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was shown to be an important pathway in the induction of autophagy in response to oxaliplatin. Autopjhagy was inhibited by 3-methyladenine and JAK2/STAT3 signaling was blocked by AG490, which induced apoptosis in SMMC7721 cells treated with oxaliplatin. The results of the present study may help to elucidate the mechanism underlying the role of IL-17/IL-17R-induced autophagy in the chemoresistance of HCC, as well as help to establish and develop measures to overcome chemoresistance in HCC.

miR-138-5p acts as a tumor suppressor by targeting hTERT in human colorectal cancer.

Colorectal cancer (CRC) is the second most common cancer in the world. The incidence of this cancer is increasing in the developing countries. Mechanism of CRC tumorigenesis has been widely studied at the molecular levels, and has been recently proposed microRNAs as novel players in CRC. It has been reported that microRNA-138-5p (miR-138-5p) play key roles in different kinds of human cancers. However, the roles and underlying molecular mechanisms of miR-138-5p in CRC have not been adequately elucidated. Thus, the aim of the present study was to investigate the roles and possible regulatory mechanisms of miR-138-5p in CRC. In this study, we demonstrated that miR-138-5p was significantly down-regulated in CRC tissue samples and cell lines. Functional analyses indicated that the overexpression of miR-138-5p significantly delayed cell proliferation, reduced colony formation and increased apoptosis in CRC cell lines. Moreover, human telomerase reverse transcriptase (hTERT), an important oncogene in the management of tumors, was confirmed as a direct target of miR-138-5p in CRC cells. We also found that the hTERT expression was increased in CRC tissues and was inversely correlated with miR-138-5p. Further study showed that the restoration of hTERT expression by an overexpressing plasmid could reverse the effects of miR-138-5p on proliferation and apoptosis of CRC cells. Taken together, these data defines a major suppresses proliferation and promotes apoptosis role for miR-138-5p, a microRNA functions as a tumor suppressor in CRC, by directly targeting hTERT, which would be provide a new strategy for future CRC therapies.

Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression of p38 and Erk MAPK pathways.

OBJECTIVE: This study aimed to investigate the role of ligustrazine on apoptosis and inflammatory reaction in acute pancreatitis. METHODS: Rats and acinar cells were treated with caerulein to induce acute pancreatitis models. Cell models were treated with saline, p38 inhibitor, Erk inhibitor and ligustrazine. Then, the levels of TNF-α, IL-1ß and IL-6 were determined by ELISA assay, the protein levels of p38, Erk1/2, p53 and cleaved caspase3 were determined by western blotting, and apoptosis were measured by flow cytometry. Rat models were treated with saline and ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity and the levels of TNF-α, IL-1ß and IL-6 in rats were determined. The protein levels of p38, Erk1/2, p53 and cleaved caspase3 in pancreas tissues were determined by western blotting, and pancreas tissues were also performed TUNEL staining to observe apoptosis status. RESULTS: Ligustrazine downregulated the levels of TNF-α, IL-1ß, IL-6. The protein levels of p38 and Erk were reduced by p38 inhibitor, Erk inhibitor and ligustrazine, while the levels of p53 and cleaved caspase 3 were upregulated. Apoptosis of AP acinar cells and cells in AP rat models was promoted after treated with ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity in AP rat models were reduced by ligustrazine. CONCLUSION: Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression on p38 and Erk MAPK pathways. It is capable of attenuating the severity of acute pancreatitis and may have a therapeutic effect on patients with acute pancreatitis.