Chemoresistance is an obstacle for colorectal cancer (CRC) treatment. This study investigates the role of the ubiquitin E3 ligase MDM2 in affecting cell growth and chemosensitivity in CRC cells by modifying the transcription factor inhibitor of growth protein 3 (ING3). The expression of MDM2 and ING3 in CRC tissues was predicted by bioinformatics analysis, followed by expression validation and their interaction in CRC HCT116 and LS180 cells. Ectopic overexpression or knockdown of MDM2/ING3 was performed to test their effect on proliferation and apotptosis as well as chemosensitivity of CRC cells. Finally, the effect of MDM2/ING3 expression on the in vivo tumorigenesis of CRC cells was examined through subcutaneous tumor xenograft experiment in nude mice. MDM2 promoted ubiquitin-proteasome pathway degradation of ING3 through ubiquitination and diminished its protein stability. Overexpression of MDM2 downregulated ING3 expression, which promoted CRC cell proliferation and inhibited the apoptosis. The enhancing role of MDM2 in tumorigenesis and resistance to chemotherapeutic drugs was also confirmed in vivo. Our findings highlight that MDM2 modifies the transcription factor ING3 by ubiquitination-proteasome pathway degradation, thus reducing ING3 protein stability, which finally promotes CRC cell growth and chemoresistance.

中文翻译：

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泛素 E3 连接酶 MDM2 通过降解 ING3 诱导结直肠癌化疗耐药。

化疗耐药是结直肠癌（CRC）治疗的一个障碍。本研究通过修饰生长蛋白 3 (ING3) 的转录因子抑制剂，探讨泛素 E3 连接酶 MDM2 在影响 CRC 细胞生长和化疗敏感性中的作用。通过生物信息学分析预测结直肠癌组织中 MDM2 和 ING3 的表达，然后在结直肠癌 HCT116 和 LS180 细胞中进行表达验证及其相互作用。对 MDM2/ING3 进行异位过表达或敲低，以测试其对 CRC 细胞增殖和凋亡以及化疗敏感性的影响。最后，通过裸鼠皮下肿瘤异种移植实验，探讨MDM2/ING3表达对CRC细胞体内致瘤的影响。MDM2 通过泛素化促进 ING3 泛素-蛋白酶体途径降解，并降低其蛋白质稳定性。MDM2过表达下调ING3表达，促进CRC细胞增殖并抑制细胞凋亡。MDM2在肿瘤发生和化疗药物耐药性中的增强作用也在体内得到证实。我们的研究结果强调，MDM2 通过泛素化-蛋白酶体途径降解修饰转录因子 ING3，从而降低 ING3 蛋白稳定性，最终促进 CRC 细胞生长和化疗耐药。