Central Laboratory, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215002, Jiangsu Province, China.
Department of Pathology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215002, Jiangsu Province, China.
Mol Cancer. 2020 Dec 1;19(1):168. doi: 10.1186/s12943-020-01285-4.
Hypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.
缺氧应激在癌症进展中起着关键作用；然而，缺氧如何驱动肿瘤变得更具侵袭性或转移性，以及对不利环境压力的适应性，仍知之甚少。在这项研究中，我们揭示了 CSN8 可能是控制缺氧诱导的恶性肿瘤进展的关键调节开关。我们表明，CSN8 的表达在结直肠癌组织中显著增加，这与淋巴结转移相关，并预测患者预后不良。CSN8 的过表达诱导结直肠癌细胞发生上皮-间充质转化（EMT）过程，增加迁移和侵袭。CSN8 的过表达抑制细胞增殖，上调关键休眠标记物（NR2F1、DEC2、p27）和缺氧反应基因（HIF-1α、GLUT1），并在缺氧、血清剥夺或化疗药物 5-氟尿嘧啶处理条件下显著增强细胞存活。特别是，沉默 CSN8 可阻断体外 1% O 缺氧诱导的 EMT 和休眠过程，并破坏结直肠癌细胞在体内的适应能力。进一步的研究表明，CSN8 通过激活 HIF-1α 信号通路部分调节 EMT 和休眠，通过激活 NF-κB 增加 HIF-1α mRNA 表达，并通过 HIF-1α 去泛素化稳定 HIF-1α 蛋白。总之，CSN8 通过调节缺氧诱导的 EMT 和休眠，赋予原发性结直肠癌细胞高度侵袭性/转移性和适应性能力。CSN8 可以作为结直肠癌的新型预后标志物，并可能成为消除播散休眠细胞和预防肿瘤转移、复发和化疗耐药的理想靶点。
