Jing Xu, Du Lutao, Shi Shuang, Niu Aijun, Wu Jing, Wang Yunshan, Wang Chuanxin
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China.
Department of Pharmacy, The Second Hospital of Shandong University, Jinan, China.
Front Pharmacol. 2022 May 16;13:806682. doi: 10.3389/fphar.2022.806682. eCollection 2022.
Hypoxia is identified as one of the microenvironmental features of most solid tumors and is involved in tumor progression. In the present research, we demonstrate that lncRNA extracellular leucine rich repeat and fibronectin type III domain-containing 1-antisense RNA 1 (ELFN1-AS1) is upregulated by hypoxia in colon cancer cells. Knockdown of ELFN1-AS1 in hypoxic colon cancer cells can reduce cell proliferation and restore the invasion to non-hypoxic levels. Fluorescence in situ hybridization results show that ELFN1-AS1 is distributed in the cytoplasm of colon cancer cells, so we further analyze the potential targets for ELFN1-AS1 as a competing endogenous RNA (ceRNA). MiR-191-5p contains a binding sequence with ELFN1-AS1 and is downregulated by ELFN1-AS1 in colon cancer cells. Then, there is a binding site between miR-191-5p and the 3' untranslated region of tripartite motif TRIM 14 (TRIM14). The expression of TRIM14 is inhibited by ELFN1-AS1 siRNA or miR-191-5p mimics in LoVo and HT29 cells. The treatment of the miR-191-5p inhibitor in ELFN1-AS1 knockdown cells can significantly increase cell proliferation and invasion ability. Overexpression of TRIM14 in miR-191-5p-mimic-treated cells can rescue the inhibition of proliferation and invasion caused by miR-191-5p mimics. In conclusion, ELFN1-AS1 operates as a downstream target of hypoxia, promotes proliferation and invasion, and inhibits apoptosis through upregulating TRIM14 by sponging miR-191-5p in the colon cancer cells. Our results enrich our understanding of colon cancer progression and provide potential targets for clinical treatment of colon cancer.
缺氧被认为是大多数实体瘤的微环境特征之一，并参与肿瘤进展。在本研究中，我们证明长链非编码RNA细胞外富含亮氨酸重复序列和III型纤连蛋白结构域1反义RNA 1（ELFN1-AS1）在结肠癌细胞中被缺氧上调。敲低缺氧结肠癌细胞中的ELFN1-AS1可减少细胞增殖并将侵袭恢复到非缺氧水平。荧光原位杂交结果显示ELFN1-AS1分布于结肠癌细胞的细胞质中，因此我们进一步分析ELFN1-AS1作为竞争性内源RNA（ceRNA）的潜在靶点。MiR-191-5p包含与ELFN1-AS1的结合序列，并且在结肠癌细胞中被ELFN1-AS1下调。然后，miR-191-5p与三方基序TRIM 14（TRIM14）的3'非翻译区之间存在结合位点。在LoVo和HT29细胞中，ELFN1-AS1 siRNA或miR-191-5p模拟物可抑制TRIM14的表达。在ELFN1-AS1敲低细胞中处理miR-191-5p抑制剂可显著增加细胞增殖和侵袭能力。在miR-191-5p模拟物处理的细胞中过表达TRIM14可挽救由miR-191-5p模拟物引起的增殖和侵袭抑制。总之，ELFN1-AS1作为缺氧的下游靶点，通过在结肠癌细胞中海绵化miR-191-5p上调TRIM14，促进增殖和侵袭并抑制凋亡。我们的结果丰富了我们对结肠癌进展的理解，并为结肠癌的临床治疗提供了潜在靶点。
