Elevated HOXA13 expression promotes the proliferation and metastasis of gastric cancer partly via activating Erk1/2
Elevated HOXA13 expression promotes the proliferation and metastasis of gastric cancer partly via activating Erk1/2
复制标题
HOXA13表达升高部分通过激活Erk1/2促进胃癌的增殖和转移
DOI：
10.2147/ott.s196986
复制
发表时间：
2019-01-01
影响因子：
4
通讯作者：
Zhou, Chongzhi
中科院分区：
文献类型：
--
作者：
Qin, Zhiwei;Chen, Zhengqian;Zhou, Chongzhi
目的HOXA 13是同源异型盒（HOX）基因家族的一个转录因子，在进化上高度保守。HOXA 13在某些癌症中上调并与致癌特性相关。本研究旨在探讨HOXA 13介导胃癌细胞增殖和转移的可能机制。方法采用实时荧光定量PCR、Western blot和免疫组化方法检测胃癌组织中HOXA 13的表达水平。进行体外和体内测定以研究HOXA 13在GC细胞增殖、迁移和侵袭中的功能。进行RNA-Seq转录组分析以研究GC中HOXA 13介导的侵袭性的潜在机制。结果胃癌组织中HOXA 13 mRNA和蛋白表达水平上调。通过细胞计数试剂盒-8和集落形成实验，我们发现HOXA 13的过表达促进了细胞的增殖。流式细胞术分析显示，HOXA 13过表达或敲低分别导致G1-S期转变或G1期停滞。Western blot分析结果显示HOXA 13过表达增加cyclin D1的表达，而敲低HOXA 13则降低其表达。创伤愈合和transwell实验结果表明HOXA 13过表达促进了胃癌细胞的迁移和侵袭。Western blot分析结果还显示HOXA 13过表达上调N-cadherin和vimentin，下调E-cadherin，而HOXA 13敲低导致相反的结果，表明HOXA 13可能参与上皮向间充质转化。这些结果通过肿瘤异种移植和转移测定在体内验证。从机制上讲，使用RNA-Seq转录组分析，我们发现Erk 1/2激活在HOXA 13诱导的GC进展中起重要作用。结论HOXA 13基因在胃癌的发生发展中起重要作用。HOXA 13过表达促进胃癌细胞的增殖和转移，部分是通过激活Erk 1/2实现的。因此，HOXA 13，连同Erk 1/2，可能是有前途的新的抗癌策略的目标。
Purpose HOXA13 is a transcription factor of the Homeobox (HOX) gene family, which is highly evolutionarily conserved. HOXA13 is upregulated and associated with oncogenic properties in some cancers. Here, we studied the potential mechanism of HOXA13-mediated proliferation and metastasis in gastric cancer (GC). Methods Quantitative real-time PCR, Western blot, and immunohistochemistry were used to detect HOXA13 expression levels in GC. In vitro and in vivo assays were performed to investigate the function of HOXA13 in GC cell proliferation, migration, and invasion. RNA-Seq transcriptome analysis was performed to study the underlying mechanism of HOXA13-mediated aggressiveness in GC. Results HOXA13 mRNA and protein expression levels were upregulated in GC tissues. According to Cell Counting Kit-8 and colony formation assays, we found that HOXA13 over-expression promoted proliferation. Flow cytometry analysis showed that HOXA13 overexpression or knockdown led to G1-S phase transition or G1 phase arrest, respectively. Western blot analysis results showed that HOXA13 overexpression increased cyclin D1 expression, while knockdown decreased its expression. Wound healing and transwell assay results demonstrated that HOXA13 overexpression promoted the migration and invasion of GC cells. Western blot analysis results also showed that HOXA13 overexpression upregulated N-cadherin and vimentin and downregulated E-cadherin, while HOXA13 knockdown led to the opposite results, indicating that HOXA13 might participate in epithelial to mesenchymal transition. These results were verified in vivo by tumor xenograft and metastasis assays. Mechanistically, using RNA-Seq transcriptome analysis, we found that Erk1/2 activation played an important role in HOXA13-induced GC progression. Conclusion Our results show that HOXA13 plays an important role in GC development. HOXA13 overexpression promotes proliferation and metastasis partly via activation of Erk1/2 in GC. Thus, HOXA13, together with Erk1/2, may be promising targets for novel anticancer strategies.