Department of Gastroenterology, Zhongnan Hospital of Wuhan University & Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal Diseases, Wuhan 430071, China.
Exp Biol Med (Maywood). 2021 Sep;246(17):1895-1906. doi: 10.1177/15353702211011576. Epub 2021 May 8.
Hypoxia, the most common feature in the tumor microenvironment, is closely related to tumor malignant progression and poor patient's prognosis. Exosomes, initially recognized as cellular "garbage dumpsters", are now known to be important mediums for mediating cellular communication in tumor microenvironment. However, the mechanisms of hypoxic tumor cell-derived exosomes facilitate colorectal cancer progression still need further exploration. In the present study, we found that exosomes from hypoxic colorectal cancer cells (H-Exos) promoted G1-S cycle transition and proliferation while preventing the apoptosis of colorectal cancer cells by transmitting miR-210-3p to normoxic tumor cells. Mechanistic investigation indicated that miR-210-3p from H-Exos elicited its protumoral effect via suppressing CELF2 expression. A preclinical study further confirmed that H-Exos could promote tumorigenesis . Clinically, the expression of miR-210-3p in circulating plasma exosomes was markedly upregulated in colorectal cancer patients, which were closely associated with multiple unfavorable clinicopathological features. Taken together, these results suggest that hypoxia may stimulate colorectal cancer cells to secrete miR-210-3p-enriched exosomes in tumor microenvironment, which elicit protumoral effects by inhibiting CELF2 expression. These findings provide new insights on the mechanism of colorectal cancer progression and potential therapeutic targets for colorectal cancer.
缺氧是肿瘤微环境中最常见的特征，与肿瘤恶性进展和患者预后不良密切相关。外泌体最初被认为是细胞的“垃圾场”，现在被认为是肿瘤微环境中细胞间通讯的重要介质。然而，缺氧肿瘤细胞来源的外泌体促进结直肠癌进展的机制仍需要进一步探索。在本研究中，我们发现缺氧结直肠癌细胞来源的外泌体（H-Exos）通过将 miR-210-3p 传递给常氧肿瘤细胞，促进 G1-S 期细胞周期转换和增殖，同时阻止结直肠癌细胞凋亡。机制研究表明，H-Exos 中的 miR-210-3p 通过抑制 CELF2 的表达发挥其促肿瘤作用。一项临床前研究进一步证实，H-Exos 可促进肿瘤发生。临床上，结直肠癌患者循环血浆外泌体中 miR-210-3p 的表达明显上调，与多种不良临床病理特征密切相关。综上所述，这些结果表明，缺氧可能刺激结直肠癌细胞在肿瘤微环境中分泌富含 miR-210-3p 的外泌体，通过抑制 CELF2 的表达发挥促肿瘤作用。这些发现为结直肠癌进展的机制提供了新的见解，并为结直肠癌提供了潜在的治疗靶点。
