N6-methyladenosine-modified long non-coding RNA KIF9-AS1 promotes stemness and sorafenib resistance in hepatocellular carcinoma by upregulating SHOX2 expression  

作　　者：Yong Yu Xiang-Hong Lu Jin-Song Mu Jiang-Yun Meng Jiang-Shan Sun Hai-Xu Chen Yang Yan Ke Meng 

机构地区：[1]Department of Gastroenterology and Hepatology,The First Medical Center,Chinese People’s Liberation Army General Hospital,Beijing 100853,China [2]Department of Intensive Care Medicine,The First Medical Center,Chinese People’s Liberation Army General Hospital,Beijing 100853,China [3]Department of Intensive Care Medicine,The Fifth Medical Center,Chinese People’s Liberation Army General Hospital,Beijing 100039,China [4]Institute of Geriatrics and National Clinical Research Center of Geriatrics Disease,The Second Medical Center,Chinese People’s Liberation Army General Hospital,Beijing 100853,China [5]Department of General Surgery,The First Medical Center,Chinese People’s Liberation Army General Hospital,Beijing 100853,China

出　　处：《World Journal of Gastroenterology》2024年第48期5174-5190,共17页世界胃肠病学杂志（英文）

基　　金：Supported by the National Natural Science Foundation of China,No.82271628.

摘　　要：BACKGROUND Hepatocellular carcinoma(HCC)is a prevalent and aggressive tumor.Sorafenib is the first-line treatment for patients with advanced HCC,but resistance to sorafenib has become a significant challenge in this therapy.Cancer stem cells play a crucial role in sorafenib resistance in HCC.Our previous study revealed that the long non-coding RNA(lncRNA)KIF9-AS1 is an oncogenic gene in HCC.However,the role of KIF9-AS1 in drug resistance and cancer stemness in HCC remains unclear.Herein,we aimed to investigate the function and mechanism of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC.AIM To describe the role of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.METHODS Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients.Sphere formation was quantified via a tumor sphere assay.Cell viability,proliferation,and apoptosis were evaluated via Cell Counting Kit-8,flow cytometry,and colony formation assays,respectively.The interactions between the lncRNA KIF9-AS1 and its downstream targets were confirmed via RNA immunoprecipitation and coimmunoprecipitation.The tumorigenic role of KIF9-AS1 was validated in a mouse model.RESULTS Compared with that in normal controls,the expression of the lncRNA KIF9-AS1 was upregulated in HCC tissues.Knockdown of KIF9-AS1 inhibited stemness and attenuated sorafenib resistance in HCC cells.Mechanistically,N6-methyladenosine modification mediated by methyltransferase-like 3/insulin-like growth factor 2 mRNA-binding protein 1 stabilized and increased the expression of KIF9-AS1.Additionally,KIF9-AS1 increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination.Furthermore,depletion of KIF9-AS1 alleviated sorafenib resistance in a xenograft mouse model of HCC.CONCLUSION The N6-methyladenosine-modified lncRNA KIF9-AS1 promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expre

关 键 词：Hepatocellular carcinoma STEMNESS Sorafenib resistance Long non-coding RNA KIF9-AS1 Short stature homeobox 2 

分 类 号：R735.7[医药卫生—肿瘤]