Knockdown of BAP31 Downregulates Galectin-3 to Inhibit the Wnt/β-Catenin Signaling Pathway to Modulate 5-FU Chemosensitivity and Cancer Stemness in Colorectal Cancer.
Knockdown of BAP31 Downregulates Galectin-3 to Inhibit the Wnt/β-Catenin Signaling Pathway to Modulate 5-FU Chemosensitivity and Cancer Stemness in Colorectal Cancer.
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DOI：
10.3390/ijms241814402
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发表时间：
2023-09-21
影响因子：
5.6
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Liu J;Zhang Q;Wang J;Wang C;Lan T;Wang T;Wang B
干性增加与癌症中化学抗性的发展有因果关系。B细胞受体相关蛋白31（BAP 31）已被鉴定为在许多类型的癌症中发挥致癌作用。然而，BAP 31在5-氟尿嘧啶（5-FU）化疗敏感性和结直肠癌（CRC）干性中的作用仍然未知。本研究旨在探讨BAP 31在调节5-FU化疗敏感性和干性中的生物学功能及其分子机制。采用3-（4，5-二甲基-2-噻唑基）-2，5-二苯基-2-H-溴化四唑和集落形成试验检测BAP 31表达与5-FU化疗敏感性之间的相关性。使用肿瘤球形成和蛋白质印迹测定分析癌症干性。通过Western blot和免疫荧光分析，探讨了其可能的作用机制。最后，我们通过构建裸鼠移植瘤模型，研究了BAP 31的功能。在这项研究中，我们证明了BAP 31在CRC细胞中增加，并且BAP 31的敲低降低了5-FU的半数最大抑制浓度（IC 50），而这种作用被BAP 31的过表达逆转。此外，BAP 31的敲除在体外显著降低了CRC细胞的干细胞性。因此，BAP 31基因的敲低可显著抑制大肠癌的体内致瘤性和干性。功能研究进一步表明，BAP 31的敲低下调galectin-3以抑制β-catenin的积累，这反过来又抑制Wnt/β-catenin信号通路的下游靶基因（c-MYC，SOX 2）的转录。BAP 31的敲低通过抑制Wnt/β-连环蛋白信号传导途径来增加5-FU化疗敏感性，从而降低了干性。重要的是，针对BAP 31的胞内抗体在体内抑制肿瘤生长并增强5-FU的抗肿瘤作用。因此，使用针对BAP 31的胞内抗体可能是提高5-FU对CRC抗肿瘤作用的一种策略。
Increased stemness is causally linked to the development of chemoresistance in cancers. B-cell receptor-associated protein 31 (BAP31) has been identified to play an oncogenic role in many types of cancer. However, the role of BAP31 in 5-fluorouracil (5-FU) chemosensitivity and stemness of colorectal cancer (CRC) is still unknown. The aim of this study was to investigate the biological function and molecular mechanism of BAP31 in regulating 5-FU chemosensitivity and stemness. The correlation between BAP31 expression and 5-FU chemosensitivity was examined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and colony formation assays. Cancer stemness was analyzed using tumor sphere formation and Western blot assays. Western blot and immunofluorescence analyses of the knockdown cell lines were performed to explore the possible mechanisms. Finally, we investigated the function of BAP31 by constructing xenograft nude mouse models in vivo. In this study, we demonstrated that BAP31 was increased in CRC cells, and knockdown of BAP31 reduced the half maximal inhibitory concentration (IC50) of 5-FU, while this effect was reversed by overexpression of BAP31. In addition, knockdown of BAP31 substantially reduced the stemness of CRC cells in vitro. Consistently, knockdown of BAP31 significantly suppressed the tumorigenicity and stemness of CRC in vivo. The functional study further suggested that knockdown of BAP31 downregulated galectin-3 to inhibit the accumulation of β-catenin, which in turn repressed the transcription of downstream target genes (c-MYC, SOX2) of the Wnt/β-catenin signaling pathway. Knockdown of BAP31 reduced stemness by inhibiting the Wnt/β-catenin signaling pathway to increase 5-FU chemosensitivity. Importantly, intrabodies against BAP31 suppressed tumor growth and enhanced the antitumor effects of 5-FU in vivo. Therefore, using intrabodies against BAP31 may be a strategy for improving the antitumor effect of 5-FU in CRC.
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影响因子：
5
作者：
Liu T;Yu J;Ge C;Zhao F;Miao C;Jin W;Su Y;Geng Q;Chen T;Xie H;Cui Y;Yao M;Li J;Hou H;Li H
通讯作者：
Li H
影响因子：
11.8
作者：
Krishnamurthy N;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
--
作者：
Chung LY;Tang SJ;Wu YC;Sun GH;Liu HY;Sun KH
通讯作者：
Sun KH
影响因子：
7.3
作者：
Huang, Xingxing;Ke, Kun;Jin, Weiwei;Zhu, Qianru;Zhu, Qicong;Mei, Ruyi;Zhang, Ruonan;Yu, Shuxian;Shou, Lan;Sun, Xueni;Feng, Jiao;Duan, Ting;Mou, Yiping;Xie, Tian;Wu, Qibiao;Sui, Xinbing
通讯作者：
Sui, Xinbing
影响因子：
2.7
作者：
Liang, Haiyan;Dong, Jiqiao;Ling, Bin
通讯作者：
Ling, Bin