ADAM12 通过 EGFR/ERK 信号通路促进肾透明细胞癌的进展并引发 EMT。
ADAM12 promotes clear cell renal cell carcinoma progression and triggers EMT via EGFR/ERK signaling pathway.
机构信息
Department of Urology, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.
Shantou University Medical College, Shantou, 515041, Guangdong, China.
出版信息
J Transl Med. 2023 Jan 30;21(1):56. doi: 10.1186/s12967-023-03913-1.
BACKGROUND
Clear cell renal cell carcinoma (ccRCC) is a major worldwide health problem due to its high prevalence and mortality rate. A disintegrin and metalloproteinase 12 (ADAM12) is aberrantly expressed in various cancers and plays an important role in tumor progression. However, its explicit effect and molecular mechanism in ccRCC remain unclear.
METHODS
We investigated the dysregulation of ADAM12 in ccRCC through public databases and bioinformatics analyses. The expression of ADAM12 was further verified in ccRCC tissues by RT-qPCR and immunohistochemistry (IHC). The relationship between ADAM12 expression and clinicopathological characteristics was analyzed statistically. The effects of ADAM12 on the proliferation, migration and invasion of ccRCC cells were examined by in vitro and in vivo experiments.
RESULTS
ADAM12 was significantly upregulated in ccRCC tissues and associated with poor prognosis in ccRCC patients. ADAM12 promoted ccRCC cell proliferation, migration and invasion in vitro and the growth of subcutaneous tumors in vivo. Knockdown of ADAM12 successfully suppressed its oncogenic function. Mechanistically, its overexpression induced epithelial-mesenchymal transition (EMT) by downregulating E-cadherin and upregulating N-cadherin and Snail. Moreover, ADAM12 participated in the epidermal growth factor receptor (EGFR) pathway and activated the downstream signal ERK1/2 by shedding the EGFR ligand, thereby upregulating target genes including c-Myc, enhancing cell survival and invasion ability, and promoting tumor progression, metastasis and the induction of EMT.
CONCLUSIONS
High expression of ADAM12 induced EMT and promoted cell proliferation, migration, and invasion by activating the EGFR/ERK signaling pathway in ccRCC.
背景
透明细胞肾细胞癌（ccRCC）由于其高患病率和死亡率，是一个全球性的主要健康问题。解整合素金属蛋白酶 12（ADAM12）在各种癌症中异常表达，在肿瘤进展中发挥重要作用。然而，其在 ccRCC 中的明确作用和分子机制尚不清楚。
方法
我们通过公共数据库和生物信息学分析研究了 ADAM12 在 ccRCC 中的失调。通过 RT-qPCR 和免疫组织化学（IHC）进一步验证了 ADAM12 在 ccRCC 组织中的表达。统计分析了 ADAM12 表达与临床病理特征的关系。通过体外和体内实验研究了 ADAM12 对 ccRCC 细胞增殖、迁移和侵袭的影响。
结果
ADAM12 在 ccRCC 组织中显著上调，并与 ccRCC 患者的不良预后相关。ADAM12 促进了 ccRCC 细胞的体外增殖、迁移和侵袭以及体内皮下肿瘤的生长。ADAM12 的敲低成功抑制了其致癌功能。机制上，其过表达通过下调 E-钙粘蛋白和上调 N-钙粘蛋白和 SNAIL 诱导上皮-间充质转化（EMT）。此外，ADAM12 参与表皮生长因子受体（EGFR）途径，通过脱落 EGFR 配体激活下游信号 ERK1/2，从而上调包括 c-Myc 在内的靶基因，增强细胞存活和侵袭能力，促进肿瘤进展、转移和 EMT 的诱导。
结论
ADAM12 的高表达通过激活 EGFR/ERK 信号通路诱导 EMT，并促进 ccRCC 中细胞的增殖、迁移和侵袭。
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