Islam Ranakul, Zhao Lei, Zhang Xiujuan, Liu Ling-Zhi
Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Cancers (Basel). 2023 Feb 14;15(4):1204. doi: 10.3390/cancers15041204.
Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear.
RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling.
EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3'-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR.
Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future.
砷是一种众所周知的致癌物，可诱发肺癌、皮肤癌、膀胱癌和肝癌。表皮生长因子受体（EGFR）表达异常在肺癌中很常见；它参与癌症的发生、发展、转移和治疗抵抗。然而，砷诱导EGFR上调的潜在机制仍不清楚。
采用逆转录-聚合酶链反应（RT-PCR）和免疫印迹分析检测miR-218-5p和EGFR的表达水平。荧光素酶报告基因检测用于检测miR-218-5p介导的EGFR转录活性。采用细胞增殖、集落形成、伤口愈合、迁移实验、管形成实验和肿瘤生长实验研究miR-218-5p/EGFR信号通路的功能。
在砷诱导的转化（As-T）细胞中，EGFR显著上调，而miR-218-5p显著下调。MiR-218-5p作为一种肿瘤抑制因子，可抑制细胞增殖、迁移、集落形成、管形成、肿瘤生长和血管生成。此外，miR-218-5p通过与EGFR的3'非翻译区（UTR）结合直接靶向EGFR。最后，miR-218-5p通过抑制其直接靶点EGFR发挥抗肿瘤作用。
我们的研究突出了miR-218-5p/EGFR信号通路在砷诱导的致癌作用和血管生成中的重要作用，这可能有助于未来治疗慢性砷暴露诱导的肺癌。
