Abstract：
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.
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.
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.
High expression of ADAM12 induced EMT and promoted cell proliferation, migration, and invasion by activating the EGFR/ERK signaling pathway in ccRCC.
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.
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.
High expression of ADAM12 induced EMT and promoted cell proliferation, migration, and invasion by activating the EGFR/ERK signaling pathway in ccRCC.
摘要：
背景：透明细胞肾细胞癌（ccRCC）由于其高患病率和死亡率而成为全球主要的健康问题。整合素和金属蛋白酶12（ADAM12）在各种癌症中异常表达，并在肿瘤进展中起重要作用。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ccRCC中ADAM12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。对ADAM12表达与临床病理特征的关系进行统计学分析。ADAM12对细胞增殖的影响,通过体外和体内实验检查ccRCC细胞的迁移和侵袭。
结果：ADAM12在ccRCC组织中显著上调，与ccRCC患者的不良预后相关。ADAM12促进ccRCC细胞增殖，体外迁移和侵袭以及体内皮下肿瘤的生长。敲除ADAM12成功抑制其致癌功能。机械上,它的过表达通过下调E-cadherin和上调N-cadherin和Snail诱导上皮-间质转化（EMT）。此外，ADAM12参与表皮生长因子受体(EGFR)通路,通过释放EGFR配体激活下游信号ERK1/2,从而上调靶基因，包括c-Myc，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高表达诱导EMT，促进细胞增殖，迁移,通过激活ccRCC中的EGFR/ERK信号通路进行侵袭。
方法：我们通过公共数据库和生物信息学分析研究了ccRCC中ADAM12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。对ADAM12表达与临床病理特征的关系进行统计学分析。ADAM12对细胞增殖的影响,通过体外和体内实验检查ccRCC细胞的迁移和侵袭。
结果：ADAM12在ccRCC组织中显著上调，与ccRCC患者的不良预后相关。ADAM12促进ccRCC细胞增殖，体外迁移和侵袭以及体内皮下肿瘤的生长。敲除ADAM12成功抑制其致癌功能。机械上,它的过表达通过下调E-cadherin和上调N-cadherin和Snail诱导上皮-间质转化（EMT）。此外，ADAM12参与表皮生长因子受体(EGFR)通路,通过释放EGFR配体激活下游信号ERK1/2,从而上调靶基因，包括c-Myc，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高表达诱导EMT，促进细胞增殖，迁移,通过激活ccRCC中的EGFR/ERK信号通路进行侵袭。
