Han Yang, Lu Su, Song Chenlong, Xuan Yi, Zhang Meng, Cai Hong
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Death Discov. 2023 Mar 9;9(1):85. doi: 10.1038/s41420-023-01386-1.
Colorectal cancer is a very heterogeneous disease caused by the interaction of genetic and environmental factors. P53, as a frequent mutation gene, plays a critical role in the adenoma-carcinoma transition during the tumorous pathological process. Our team discovered TRIM3 as a tumor-associated gene in CRC by high-content screening techniques. TRIM3 demonstrated both tumor-suppressive and tumorigenic features in cell experiments dependent on the cell status of wild or mutant p53. TRIM3 could directly interact with the C terminus of p53 (residues 320 to 393), a common segment of wtp53 and mutp53. Moreover, TRIM3 could exert different neoplastic features by retaining p53 in the cytoplasm to decrease its nuclear expression in a wtp53 or mutp53-dependent pathway. Chemotherapy resistance develops in nearly all patients with advanced CRC and seriously limits the therapeutic efficacies of anticancer drugs. TRIM3 could reverse the chemotherapy resistance of oxaliplatin in mutp53 CRC cells by degradation of mutp53 in the nuclei to downregulate the multidrug resistance gene. Therefore, TRIM3 could be a potential therapeutic strategy to improve the survival of CRC patients with mutp53.
结直肠癌是一种由遗传和环境因素相互作用引起的高度异质性疾病。P53作为一种常见的突变基因，在肿瘤病理过程中的腺瘤-癌转变中起关键作用。我们的团队通过高内涵筛选技术发现TRIM3是结直肠癌中的一种肿瘤相关基因。在细胞实验中，TRIM3根据野生型或突变型p53的细胞状态表现出肿瘤抑制和致瘤特征。TRIM3可直接与p53的C末端（第320至393位氨基酸残基）相互作用，这是野生型p53和突变型p53的共同区域。此外，TRIM3可通过在野生型p53或突变型p53依赖的途径中将p53保留在细胞质中以降低其核表达，从而发挥不同的肿瘤形成特征。几乎所有晚期结直肠癌患者都会出现化疗耐药，这严重限制了抗癌药物的治疗效果。TRIM3可通过降解细胞核中的突变型p53以下调多药耐药基因，从而逆转突变型p53结直肠癌细胞对奥沙利铂的化疗耐药性。因此，TRIM3可能是提高具有突变型p53的结直肠癌患者生存率的一种潜在治疗策略。
