Yong Yu, Xiang-Hong Lu, Jin-Song Mu, Jiang-Yun Meng, Jiang-Shan Sun, Hai-Xu Chen, Yang Yan, Ke Meng
{"title":"n6 -甲基腺苷修饰的长链非编码RNA KIF9-AS1通过上调SHOX2表达促进肝细胞癌的干性和索拉非尼耐药。","authors":"Yong Yu, Xiang-Hong Lu, Jin-Song Mu, Jiang-Yun Meng, Jiang-Shan Sun, Hai-Xu Chen, Yang Yan, Ke Meng","doi":"10.3748/wjg.v30.i48.5174","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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) <i>KIF9-AS1</i> is an oncogenic gene in HCC. However, the role of <i>KIF9-AS1</i> in drug resistance and cancer stemness in HCC remains unclear. Herein, we aimed to investigate the function and mechanism of the lncRNA <i>KIF9-AS1</i> in cancer stemness and drug resistance in HCC.</p><p><strong>Aim: </strong>To describe the role of the lncRNA <i>KIF9-AS1</i> in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.</p><p><strong>Methods: </strong>Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients. Sphere formation was quantified <i>via</i> a tumor sphere assay. Cell viability, proliferation, and apoptosis were evaluated <i>via</i> Cell Counting Kit-8, flow cytometry, and colony formation assays, respectively. The interactions between the lncRNA <i>KIF9-AS1</i> and its downstream targets were confirmed <i>via</i> RNA immunoprecipitation and coimmunoprecipitation. The tumorigenic role of <i>KIF9-AS1</i> was validated in a mouse model.</p><p><strong>Results: </strong>Compared with that in normal controls, the expression of the lncRNA <i>KIF9-AS1</i> was upregulated in HCC tissues. Knockdown of <i>KIF9-AS1</i> 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 <i>KIF9-AS1</i>. Additionally, <i>KIF9-AS1</i> increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination. Furthermore, depletion of <i>KIF9-AS1</i> alleviated sorafenib resistance in a xenograft mouse model of HCC.</p><p><strong>Conclusion: </strong>The N6-methyladenosine-modified lncRNA <i>KIF9-AS1</i> promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.</p>","PeriodicalId":23778,"journal":{"name":"World Journal of Gastroenterology","volume":"30 48","pages":"5174-5190"},"PeriodicalIF":4.3000,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612700/pdf/","citationCount":"0","resultStr":"{\"title\":\"N6-methyladenosine-modified long non-coding RNA <i>KIF9-AS1</i> promotes stemness and sorafenib resistance in hepatocellular carcinoma by upregulating SHOX2 expression.\",\"authors\":\"Yong Yu, Xiang-Hong Lu, Jin-Song Mu, Jiang-Yun Meng, Jiang-Shan Sun, Hai-Xu Chen, Yang Yan, Ke Meng\",\"doi\":\"10.3748/wjg.v30.i48.5174\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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) <i>KIF9-AS1</i> is an oncogenic gene in HCC. However, the role of <i>KIF9-AS1</i> in drug resistance and cancer stemness in HCC remains unclear. Herein, we aimed to investigate the function and mechanism of the lncRNA <i>KIF9-AS1</i> in cancer stemness and drug resistance in HCC.</p><p><strong>Aim: </strong>To describe the role of the lncRNA <i>KIF9-AS1</i> in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.</p><p><strong>Methods: </strong>Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients. Sphere formation was quantified <i>via</i> a tumor sphere assay. Cell viability, proliferation, and apoptosis were evaluated <i>via</i> Cell Counting Kit-8, flow cytometry, and colony formation assays, respectively. The interactions between the lncRNA <i>KIF9-AS1</i> and its downstream targets were confirmed <i>via</i> RNA immunoprecipitation and coimmunoprecipitation. The tumorigenic role of <i>KIF9-AS1</i> was validated in a mouse model.</p><p><strong>Results: </strong>Compared with that in normal controls, the expression of the lncRNA <i>KIF9-AS1</i> was upregulated in HCC tissues. Knockdown of <i>KIF9-AS1</i> 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 <i>KIF9-AS1</i>. Additionally, <i>KIF9-AS1</i> increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination. Furthermore, depletion of <i>KIF9-AS1</i> alleviated sorafenib resistance in a xenograft mouse model of HCC.</p><p><strong>Conclusion: </strong>The N6-methyladenosine-modified lncRNA <i>KIF9-AS1</i> promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.</p>\",\"PeriodicalId\":23778,\"journal\":{\"name\":\"World Journal of Gastroenterology\",\"volume\":\"30 48\",\"pages\":\"5174-5190\"},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2024-12-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612700/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"World Journal of Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3748/wjg.v30.i48.5174\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"World Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3748/wjg.v30.i48.5174","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
N6-methyladenosine-modified long non-coding RNA KIF9-AS1 promotes stemness and sorafenib resistance in hepatocellular carcinoma by upregulating SHOX2 expression.
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 expression.
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