Yu Jianwei, Deng Xueqiong, Lin Xueqin, Xie Li, Guo Sisi, Lin Xiaoliang, Lin Dong
Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China.
J Pharm Pharmacol. 2025 May 2;77(5):698-713. doi: 10.1093/jpp/rgae104.
Dystonin (DST), a potential tumor suppressor gene, plays a crucial role in regulating cancer cell proliferation and resistance to chemotherapy. However, DST's specific role in colorectal cancer (CRC) has not been thoroughly investigated, and this study aims to elucidate its molecular role in modulating cisplatin (DDP) resistance in CRC.
DST expression was analyzed in CRC tumors, DDP-resistant CRC tissues, paracancer tissues, and normal tissues. Lentiviral overexpression and shRNA knockdown were conducted in advanced CRC and DDP-resistant cell lines to assess cell viability, apoptosis, invasion, migration, proliferation, and angiogenesis. Xenograft mouse models studied DST's impact on CRC tumor growth and DDP resistance in vivo.
DST expression was significantly reduced in CRC tumor and DDP-resistant CRC tissues compared to paracancer and normal tissues (P < .001). Upregulating DST inhibited CRC and DDP-resistant cell viability, proliferation, invasion, and migration while promoting apoptosis. DST overexpression also reduced angiogenesis and attenuated DDP-induced cytotoxicity in CRC cells. Mechanistically, DST upregulation suppressed DDP resistance in CRC cells via the PI3K/Akt signaling pathway. DST upregulation reduced CRC tumor growth and mitigated DDP resistance, in vivo.
DST plays a crucial role in limiting CRC progression and overcoming DDP resistance, suggesting potential for targeted CRC therapies.
张力蛋白（DST）作为一种潜在的肿瘤抑制基因，在调节癌细胞增殖和化疗耐药性方面发挥着关键作用。然而，DST在结直肠癌（CRC）中的具体作用尚未得到充分研究，本研究旨在阐明其在调节CRC顺铂（DDP）耐药性中的分子作用。
分析DST在CRC肿瘤、DDP耐药CRC组织、癌旁组织和正常组织中的表达。在晚期CRC和DDP耐药细胞系中进行慢病毒过表达和shRNA敲低，以评估细胞活力、凋亡、侵袭、迁移、增殖和血管生成。异种移植小鼠模型研究了DST对CRC肿瘤生长和体内DDP耐药性的影响。
与癌旁组织和正常组织相比，CRC肿瘤和DDP耐药CRC组织中DST表达显著降低（P <.001）。上调DST可抑制CRC和DDP耐药细胞的活力、增殖、侵袭和迁移，同时促进凋亡。DST过表达还可减少血管生成，并减弱DDP对CRC细胞的细胞毒性。机制上，DST上调通过PI3K/Akt信号通路抑制CRC细胞中的DDP耐药性。在体内，DST上调可减少CRC肿瘤生长并减轻DDP耐药性。
DST在限制CRC进展和克服DDP耐药性方面起着关键作用，提示其在CRC靶向治疗中的潜力。
