Ren Yansong, Deng Ruxia, Cai Rui, Lu Xiansheng, Luo Yuejun, Wang Ziyuan, Zhu Yuchen, Yin Mengyuan, Ding Yanqing, Lin Jie
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.
Carcinogenesis. 2020 Dec 31;41(12):1755-1766. doi: 10.1093/carcin/bgaa038.
Tumor suppressor candidate 3 (TUSC3) is a coding gene responsible for N-glycosylation of many critical proteins. TUSC3 gene plays an oncogenic role in colorectal cancer (CRC), however, the role of TUSC3 in drug resistance of CRC is still unclear. The aim of this study is to investigate the biological function and molecular mechanism of TUSC3 in CRC drug resistance. The expression of TUSC3 in CRC is positively correlated to tumor stage in 90 paired clinical samples, and negatively associated with overall survival and disease-free survival of CRC patients. In vitro, TUSC3 promotes the formation of stemness and induces the drug resistance to 5-fluorouracil and cis-dichlorodiammineplatinum(II) in CRC cells. The tissue microarray assay and bioinformatic analysis indicate that TUSC3 may promote the expression of CD133 and ABCC1 via Hedgehog signaling pathway. Treatment of Hedgehog signaling pathway agonist or inhibitor in TUSC3-silenced or TUSC3-overexpressed cells reverse the effects of TUSC3 in cellular stemness phenotype and drug resistance. Meanwhile, coimmunoprecipitation and immunofluorescence assays indicate a tight relationship between TUSC3 and SMO protein. Our data suggest that TUSC3 promotes the formation of cellular stemness and induces drug resistance via Hedgehog signaling pathway in CRC.
肿瘤抑制候选基因3（TUSC3）是一个编码基因，负责许多关键蛋白的N-糖基化。TUSC3基因在结直肠癌（CRC）中发挥致癌作用，然而，TUSC3在CRC耐药中的作用仍不清楚。本研究的目的是探讨TUSC3在CRC耐药中的生物学功能和分子机制。在90对临床样本中，CRC中TUSC3的表达与肿瘤分期呈正相关，与CRC患者的总生存期和无病生存期呈负相关。在体外，TUSC3促进CRC细胞干性的形成，并诱导其对5-氟尿嘧啶和顺二氯二氨铂（II）产生耐药性。组织芯片分析和生物信息学分析表明，TUSC3可能通过Hedgehog信号通路促进CD133和ABCC1的表达。在TUSC3沉默或过表达的细胞中，用Hedgehog信号通路激动剂或抑制剂处理可逆转TUSC3在细胞干性表型和耐药性方面的作用。同时，免疫共沉淀和免疫荧光分析表明TUSC3与SMO蛋白之间存在紧密关系。我们的数据表明，TUSC3通过Hedgehog信号通路促进CRC细胞干性的形成并诱导耐药性。
