SQSTM1/p62 in intrahepatic cholangiocarcinoma promotes tumor progression via epithelial–mesenchymal transition and mitochondrial function maintenance. (8th June 2022)

• Record Type: Journal Article
• Authors: Chen, Jiafeng; Gao, Zheng; Li, Xiaogang; Shi, Yinghong; Tang, Zheng; Liu, Weiren; Zhang, Xin; Huang, Ao; Luo, Xuanming; Gao, Qiang; Ding, Guangyu; Song, Kang; Zhou, Jian; Fan, Jia; Fu, Xiutao; Ding, Zhenbin
• Is Part Of: Cancer medicine. Volume 12:Number 1(2023)
• Page Start: 459
• Page End: 471
• Publication Date: 2022-06-08
• Subjects: EMT -- intrahepatic cholangiocarcinoma -- metastasis -- mitophagy -- SQSTM1/p62; 616.994005
• DOI: 10.1002/cam4.4908
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: SQSTM1/p62 is a selective autophagy receptor that regulates multiple signaling pathways participating in the initiation and progression of tumors. Metastasis is still the main cause for intrahepatic cholangiocarcinoma (ICC)‐associated mortality. Hence, this study aimed to explore the mechanism of p62 promoting the progression of ICC. Methods: Western blotting and immunohistochemical analyses were conducted to detect the expression level of protein p62 in ICC tissues and its correlation with prognosis. Subsequently, the loss‐of‐function experiments in vitro and in vivo were performed to define the role of p62 in ICC cell proliferation, invasion, and metastasis. Then, the effect of p62 knockdown on mitochondrial function and mitophagy was evaluated by measuring the oxygen consumption rate, and using immunofluorescence and western blotting analyses. Results: The expression of p62 was significantly upregulated in ICC specimens compared with normal tissues. We further illustrated that p62 expression positively correlated with lymph node metastasis and poor prognosis. The loss‐of‐function assays revealed that p62 not only promoted ICC cell proliferation, migration, and invasive capacities in vitro, but also induced lung metastasis in the xenograft mouse model. Mechanistically, high expression of p62‐induced epithelial–mesenchymal transition (EMT) with the upregulation of Snail, vimentin, N‐cadherin, and downregulation of E‐cadherin. Moreover, the autophagy‐dependent function of p62 might play a vital role in maintaining the mitochondrial function of ICC by mitophagy which might further promote EMT. Conclusion: These data provided new evidence for the mechanism by which abundant p62 expression promoted ICC progression, suggesting a promising therapeutic target for antimetastatic strategies in patients with ICC. Abstract : SQSTM1/p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lymph‐node metastasis in vivo by inducing epithelial‐mesenchymal transition process. And the autophagy‐dependent function of p62 may play a vital role in EMT of ICC by mitophagy.