Aims: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. Methods and Results: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. Conclusion: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

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The human ether-a-go-go-related potassium channel 1 (hERG1) is a component of the voltage-gated Kv11.1 potassium channel, which has been recently indicated to have a crucial role in the tumorigenesis of multiple tumors, including pancreatic carcinoma. Pancreatic carcinoma is one of the most malignant human cancer types, which has an extremely poor prognosis. The present study demonstrated that the expression levels of hERG1 were markedly elevated in pancreatic cancer tissues and pancreatic cancer cell lines, and that the abnormal hERG1 expression was significantly associated with the proliferation and invasion ability of pancreatic cancer. Furthermore, hERG1 was identified to be a direct target of miR-493, which is generally reduced in pancreatic cancer tissues and cell lines. These findings provide a novel insight into the regulatory mechanism of miR-493/hERG1 in pancreatic cancer cell proliferation and invasion, which may aid the development of novel diagnostic and therapeutic strategies for pancreatic cancer in the future.

The human ether-ago go related potassium channel 1 (hERG1) is a functional component of the voltage-gated Kv11.1 potassium channel, which is commonly described as a crucial factor in the tumorigenesis of a variety of tumors. Ovarian cancer is one of the most severe types of cancer, with an extremely poor prognosis. Advances have been made in recent years; however, drug resistance and tumor recurrence remain critical issues underlying satisfactory treatment outcomes. Therefore, more effective antitumor agents with low levels of drug resistance for ovarian cancer treatment are urgently required in clinical practice. In the present study, hERG1 mRNA expression in ovarian tumor tissues and cell lines were measured by reverse transcription-quantitative polymerase chain reaction. Immunohistochemistry and western blotting were used to assess the expression levels of hERG1 protein. Cell proliferation, migration and invasion were assessed by Cell Counting Kit-8 assay and Transwell assay. A tumor xenograft assay was used to determine the growth of tumors in vivo. It was demonstrated that the expression levels of hERG1 were significantly elevated in ovarian cancer tissues and expressed in ovarian cancer cell lines, particularly in SKOV3 cells. Abnormal hERG1 expression was significantly associated with the proliferation, migration and invasion abilities of ovarian cancer. In addition, berberine (BBR) may be used as a potential drug in the treatment of ovarian cancer, possibly due to its inhibitory effects on the hERG1 channels. In conclusion, the present study demonstrated that hERG1 may be a potential therapeutic target in the treatment of ovarian cancer and provided novel insights into the mechanism underlying the antitumor effects of BBR in ovarian cancer.

Hepatic fibrosis was one of the causes to hepatocellular cancer (HCC), owing to limited therapeutic options. And hepatocytes can induce liver fibrogenesis via epithelial-mesenchymal transition (EMT). Multiple circRNAs exert critical role in the occurrence of liver fibrosis via working as microRNA (miRNA) sponges. Circ_0072088 is upregulated in hepatocellular cancer (HCC) and promote proliferation, migration of HCC cells. However, the potential research mechanism for circ_0072088 action against the fibrotic progression remain still unknown. The treatment of AML12 hepatocytes with TGF-β1 contributed to dramatically increased in the levels of circ_0072088. Additionally, in terms of mechanism, circ_0072088 was authenticated to function as miR-330-3p sponge, not only noticeable increase EMT, but also induced fibrosis in AML12 hepatocytes. MiR-330-3p could weaken the roles of circ_0072088 acceleration. Moreover, we proved that CDK1, a miR-330-3p target, was time-dependently augmented in the TGF-β1 treated AML12 hepatocytes, and its overexpression weakens the miR-330-3p regulatory effects.Our findings provided a unique role of the circ_0072088 mediates hepatic fibrosis renders epithelial-mesenchymal transition at least partially through miR-330-3p/CDK1 axis, thus suggesting its tremendous therapeutic potential in the treatment of liver diseases.