Guo S T, Guo X Y, Wang J, Wang C Y, Yang R H, Wang F H, Li X Y, Hondermarck H, Thorne R F, Wang Y F, Jin L, Zhang X D, Jiang C C
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Shanxi, China.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
Oncogenesis. 2017 May 15;6(5):e335. doi: 10.1038/oncsis.2017.37.
Despite advances in early diagnosis and the development of molecularly targeted therapy, curative treatment of colon cancer once it has metastasized is yet to be accomplished. This is closely associated with deregulated CRC cell proliferation and resistance to apoptosis. Here we reveal that upregulation of microRNA-645 (miR-645) through DNA copy number gain is responsible for enhanced proliferation and resistance to apoptosis in colon cancer. MiR-645 was upregulated in most colon cancer tissues related to adjacent normal mucosa. This appeared to be associated with amplification of a section of chromosome 20q13.13, where miR-645 is located. Inhibition of miR-645 reduced proliferation and enhanced sensitivity to apoptosis triggered by the chemotherapeutic drugs 5-fluorouracil and cisplatin in CRC cells, and retarded colon cancer xenograft growth. Conversely, overexpression of miR-645 in normal colon epithelial cells enhanced proliferation and triggered anchorage-independent cell growth. Although SRY-related HMG-box 30 (SOX30) was identified as a miR-645 target, its expression was only partially affected by miR-645, suggesting that miR-645 is a fine-tuning mechanism of SOX30 expression. Moreover, overexpression of SOX30 only moderately inhibited promotion of CRC cell proliferation by miR-645, indicating that miR-645 may have more targets that contribute to its pro-proliferation effect in colon cancer. Together, this study reveals that miR-645 can regulate oncogenesis in colon cancer with SOX30 being one of its targets.
尽管早期诊断取得了进展，分子靶向治疗也不断发展，但结肠癌一旦发生转移，其根治性治疗仍未实现。这与CRC细胞增殖失调和对凋亡的抗性密切相关。在此，我们揭示通过DNA拷贝数增加导致的microRNA-645（miR-645）上调是结肠癌增殖增强和抗凋亡的原因。在大多数与相邻正常黏膜相关的结肠癌组织中，miR-645上调。这似乎与20q13.13染色体区域（miR-645所在位置）的扩增有关。抑制miR-645可降低CRC细胞的增殖，并增强其对化疗药物5-氟尿嘧啶和顺铂引发的凋亡的敏感性，还可延缓结肠癌异种移植瘤的生长。相反，在正常结肠上皮细胞中过表达miR-645可增强增殖并引发非锚定依赖性细胞生长。尽管SRY相关的HMG盒30（SOX30）被确定为miR-645的靶标，但其表达仅受到miR-645的部分影响，这表明miR-645是SOX30表达的一种微调机制。此外，SOX30的过表达仅适度抑制miR-645对CRC细胞增殖的促进作用，这表明miR-645可能还有更多靶标有助于其在结肠癌中的促增殖作用。总之，本研究揭示miR-645可通过SOX30作为其靶标之一来调节结肠癌的肿瘤发生。
