TUSC3 induces drug resistance and cellular stemness via Hedgehog signaling pathway in colorectal cancer
TUSC3 induces drug resistance and cellular stemness via Hedgehog signaling pathway in colorectal cancer
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TUSC3 通过 Hedgehog 信号通路诱导结直肠癌耐药性和细胞干性
DOI：
10.1093/carcin/bgaa038
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发表时间：
2020-12-01
期刊：
影响因子：
4.7
通讯作者：
Lin, Jie
中科院分区：
文献类型：
--
作者：
Ren, Yansong;Deng, Ruxia;Lin, Jie
肿瘤抑制因子候选基因3（Tumor suppressor candidate 3，TUSC 3）是一个负责许多关键蛋白质N-糖基化的编码基因。TUSC 3基因在结直肠癌中具有致瘤作用，但其在结直肠癌耐药中的作用尚不清楚。本研究旨在探讨TUSC 3在大肠癌耐药中的生物学功能及其分子机制。在90例配对的临床样本中，TUSC 3在结直肠癌中的表达与肿瘤分期呈正相关，与结直肠癌患者的总生存期和无病生存期呈负相关。在体外，TUSC 3促进干细胞的形成，并诱导CRC细胞对5-氟尿嘧啶和顺式二氯二氨铂（II）的耐药性。组织芯片和生物信息学分析表明，TUSC 3可能通过Hedgehog信号通路促进CD 133和ABCC 1的表达。在TUSC 3沉默或TUSC 3过表达的细胞中处理Hedgehog信号传导途径激动剂或抑制剂逆转了TUSC 3在细胞干性表型和耐药性中的作用。同时，免疫共沉淀和免疫荧光分析表明TUSC 3和SMO蛋白之间存在紧密的关系。我们的数据表明，TUSC 3促进细胞干性的形成，并通过Hedgehog信号通路诱导CRC的耐药性。
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.