摘要
同源盒(homeobox,HOX)基因家族由包含同源盒结构域(homeodomain)的转录因子组成,其表达失调与多种癌症的发生发展有关。HOXC8作为HOX家族成员之一,它的表达可促进乳腺癌细胞的增殖与转移等。为进一步探索HOXC8在乳腺癌中的作用机制,通过转录组测序、Western blot和实时荧光定量PCR等实验发现,在乳腺癌细胞中HOXC8可上调生长分化因子15(GDF15)的表达。通过染色质免疫沉淀及荧光素酶报告等实验,证明了HOXC8可结合到GDF15基因的启动子上,作为转录因子来激活GDF15的表达。在乳腺癌细胞中,GDF15的表达能显著增强细胞的活力,促进锚定非依赖性生长、迁移以及细胞板状伪足/丝状伪足的形成。进一步证明,在乳腺癌细胞中HOXC8是通过诱导GDF15表达促进细胞生长和迁移的。此外,通过已知的肿瘤数据库分析,该研究发现在高侵袭性乳腺癌标本中HOXC8及GDF15基因均显示较高的扩增频率,且二者表达水平的上调与乳腺癌患者的预后不良呈显著的相关性。根据上述实验数据,该研究认为HOXC8-GDF15轴在乳腺癌的进展中起着重要作用,有望成为乳腺癌治疗的新靶点。
HOX(homeobox)gene family consists of homeodomain-containing transcription factors and their dysregulation is related to development of various cancers.Previously,it had been reported that HOXC8 which was a member of HOX gene family,promoted migration and metastasis of breast cancer cells.HOXC8 expression was found by RNA-seq,Western blot and RT-PCR analyses to result in up-regulation of GDF15(growth and differentiation factor 15)in breast cancer cells.HOXC8 was demonstrated by chromatin immunoprecipitation and luciferase assays to bind to the promoter of GDF15.As transcription factor,it was to activate GDF15 expression.Moreover,GDF15 expression promoted cell viability,anchorage-independent growth,migration and the formation of filopodium/lamellipodium of breast cancer cells.It was further demonstrated that HOXC8 promoted cell growth and migration by inducing GDF15 expression in breast cancer cells.Additionally,HOXC8 or GDF15 gene was amplified in invasive breast cancer and up-regulation of HOXC8 or GDF15 was statistically associated with poor prognosis of breast cancer patients.Altogether,this study showed that HOXC8-GDF15 axis played an important role in breast cancer progression and might present a promising target for breast cancer treatment.
作者
史佳璐
许珊珊
陈荣
陈倩
李勇
SHI Jialu;XU Shanshan;CHEN Rong;CHEN Qian;LI Yong(School of Life Sciences,Anhui University,Hefei 230601,China)
出处
《中国细胞生物学学报》
CAS
CSCD
2021年第10期1952-1963,共12页
Chinese Journal of Cell Biology
基金
安徽大学科研建设经费(批准号:J01006039)
安徽省人社厅“留学人员科技项目择优资助”(批准号:皖人社函[2013]385号)资助的课题。
