Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway.
Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway.
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Sec62 通过激活 Wnt/β-catenin 通路促进人类结直肠癌的干细胞性和化疗耐药性
DOI：
10.1186/s13046-021-01934-6
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发表时间：
2021-04-15
期刊：
影响因子：
--
通讯作者：
Xing B
中科院分区：
文献类型：
--
作者：
Liu X;Su K;Sun X;Jiang Y;Wang L;Hu C;Zhang C;Lu M;Du X;Xing B
背景肿瘤干细胞（CSC）相关的化疗耐药导致结直肠癌（CRC）患者预后不良.本研究旨在寻找大肠癌耐药相关分子，并阐明其作用机制，为大肠癌的治疗提供新的靶点。我们重点关注Sec 62，一个新的目标与显着增加的表达在化疗耐药的CRC组织，并进一步研究其在CRC的progress.MethodsThrough分析化疗耐药和化疗敏感的CRC之间的差异表达的基因，我们选择Sec 62作为一个新的化疗耐药相关的CRC靶点。采用免疫印迹和免疫组化方法检测Sec 62在大肠癌组织和细胞系中的表达及临床意义。Sec 62在耐药性，干性和肿瘤发生中的作用进行了评估，在体外和体内使用功能实验。采用GST pull-down、western blot、免疫共沉淀和Me-RIP等方法进一步探讨Sec 62表达上调的分子机制。Sec 62的耗尽使CRC细胞对化疗药物敏感。Sec 62通过激活Wnt/β-catenin信号通路促进CRC细胞的干细胞化。Sec 62与β-catenin结合并抑制β-catenin的降解。Sec 62竞争性地破坏β-catenin和APC之间的相互作用以抑制β-catenin破坏复合物的组装。结论胃黏膜L3介导的m6 A修饰上调了Sec 62的表达，通过与β-catenin结合，增强Wnt信号通路，促进了大肠癌的干性和化疗耐药性。因此，m6 A修饰-Sec 62-β-catenin分子轴可能成为改善CRC治疗的治疗靶点。
BackgroundCancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC.MethodsThrough analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms.ResultsSec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA.ConclusionsSec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.
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影响因子：
24.5
作者：
Chen J;Rajasekaran M;Xia H;Zhang X;Kong SN;Sekar K;Seshachalam VP;Deivasigamani A;Goh BK;Ooi LL;Hong W;Hui KM
通讯作者：
Hui KM
影响因子：
5.6
作者：
Dermani, Fatemeh Karimi;Amini, Razieh;Najafi, Rezvan
通讯作者：
Najafi, Rezvan
影响因子：
16
作者：
Ji, Lei;Lu, Bo;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
5.8
作者：
Mendoza-Topaz C;Mieszczanek J;Bienz M
通讯作者：
Bienz M
影响因子：
28.2
作者：
Hagerstrand D;Tong A;Schumacher SE;Ilic N;Shen RR;Cheung HW;Vazquez F;Shrestha Y;Kim SY;Giacomelli AO;Rosenbluh J;Schinzel AC;Spardy NA;Barbie DA;Mermel CH;Weir BA;Garraway LA;Tamayo P;Mesirov JP;Beroukhim R;Hahn WC
通讯作者：
Hahn WC