Mansour Mohammed A, Senga Takeshi
Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt; Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550 Japan.
Int J Biochem Cell Biol. 2017 Jul;88:1-13. doi: 10.1016/j.biocel.2017.04.011. Epub 2017 Apr 27.
Homeobox (HOX) genes are conserved transcription factors which determine the anterior-posterior body axis patterning. HOXD8 is a member of HOX genes deregulated in several tumors such as lung carcinoma, neuroblastoma, glioma and colorectal cancer (CRC) in a context-dependent manner. In CRC, HOXD8 is downregulated in cancer tissues and metastatic foci as compared to normal tissues. Whether HOXD8 acts as a tumor suppressor of malignant progression and metastasis is still unclear. Also, the underlying mechanism of its function including the downstream targets is totally unknown. Here, we clarified the lower expression of HOXD8 in clinical colorectal cancer vs. normal colon tissues. Also, we showed that stable expression of HOXD8 in colorectal cancer cells significantly reduced the cell proliferation, anchorage-independent growth and invasion. Further, using The Cancer Genome Atlas (TCGA), we identified the genes associated with HOXD8 in order to demonstrate its function as a suppressor or a promoter of colorectal carcinoma. Among inversely related genes, apoptotic inhibitors like STK38 kinase and MYC were shown to be negatively associated with HOXD8. We demonstrated the ability of HOXD8 to upregulate executioner caspases 6 & 7 and cleaved PARP, thus inducing the apoptotic events in colorectal cancer cells.
同源框（HOX）基因是保守的转录因子，可决定前后体轴模式。HOXD8是HOX基因家族的成员，在肺癌、神经母细胞瘤、胶质瘤和结直肠癌（CRC）等多种肿瘤中以依赖于上下文的方式失调。在结直肠癌中，与正常组织相比，HOXD8在癌组织和转移灶中表达下调。HOXD8是否作为恶性进展和转移的肿瘤抑制因子仍不清楚。此外，其功能的潜在机制，包括下游靶点，完全未知。在这里，我们阐明了HOXD8在临床结直肠癌与正常结肠组织中的低表达。此外，我们表明，HOXD8在结直肠癌细胞中的稳定表达显著降低了细胞增殖、非锚定依赖性生长和侵袭。此外，利用癌症基因组图谱（TCGA），我们鉴定了与HOXD8相关的基因，以证明其作为结直肠癌抑制因子或促进因子的功能。在负相关基因中，凋亡抑制剂如STK38激酶和MYC与HOXD8呈负相关。我们证明了HOXD8上调执行蛋白半胱天冬酶6和7以及切割的PARP的能力，从而在结直肠癌细胞中诱导凋亡事件。
