HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma

Abstract

Background: HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colorectal cancer (CRC), is mostly unknown. Methods: The HOXD9 protein expression levels were analyzed using immunofluorescence, immunohistochemistry (IHC) assays, and western blot. The in vivo and in vitro roles of HOXD9 in CRC were determined using colony formation and EdU incorporation, CCK-8, wound scratch and transwell invasion assay, and animal models. Results: Expression of HOXD9 was higher in CRC than in matched healthy tissues.High expression of HOXD9 has significantly associated with the American Joint Committee on Cancer (AJCC) stages, tumor differentiation, lymph node metastasis, and other serious invasions, and it had a poor prognosis. In vitro, HOXD9 encouraged proliferation, movement and EMT processes in cells of CRC. Also, TGF-β1 promoted the expression of HOXD9 and this effect was dependent on the dose and downregulation of HOXD9 repressed TGF-β1 -induced EMT. In vivo, HOXD9 promoted the invasive and metastasis of CRC cells via orthotopic implantation. Conclusions: The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo. | 3933 LIU et aL How to cite this article: Liu M, Xiao Y, Tang W, et al. HOXD9 promote epithelial-mesenchymal transition and metastasis in colorectal carcinoma.

Identification and development of a novel invasion-related gene signature for prognosis prediction in colon adenocarcinoma

“…The transcription factor HOXD9 is a member of the HOX family and plays an important role in tumorigenesis. By exploring the regulatory mechanism of HOXD9 on a molecular level, HOXD9 overexpression was found to significantly enhance the migration, invasion, and metastasis of hepatoma cells, gastric cancer cells, cervical cancer cells, and CRC cells [ 26 – 30 ]. The TSPAN11 protein has not been thoroughly studied in tumors.…”

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

“…Three studies reported that patients with high HOX (B7, B9, C6) protein expression levels demonstrated signi cantly advanced T status in comparison with patients with low expression, [24,25,31], (table 1). Similarly, regarding N status, 6 studies showed that the percentage of patients with regional lymph node invasion was signi cantly increased in the high HOX expression group for the following: HOXA3, A9, B8, B9, B13, C6, D1 and D9 [21,25,30,32,41,44]. Inverse correlation between HOX expression and nodal invasion was demonstrated only for HOΧD10 by Wang et al [26](table 1).…”

“…Eight studies investigated the presence of metastatic disease according to HOX expression levels [24, 25, 27-30, 33, 44]. Two studies by Liao et al [31] and Huang et al [30] for HOXB7 and B9 respectively, reported that signi cantly more patients had metastatic disease in the high HOX expression group in comparison with the low expression one, ( [21,23,31,44]. For HOXB9 studies by Zhan et al [29] and Huang et al [30] reported equivocal ndings, (table 1).…”

Roles of the HOX Proteins in Cancer Invasion and Metastasis

“…Currently, there are some reports proposing an involvement of HOX proteins in the EMT process, with an impact on the capacity of invasion and metastasis of cancer cells [73][74][75][76]. It has been demonstrated that CDH1 expression is transcriptionally upregulated by the direct binding of HOXA5 to their promoter sequence and that the knockdown of HOXA5 in mammary cells leads to a loss of epithelial traits, increased stemness and cell plasticity, and acquisition of more aggressive phenotypes [77].…”

“…Abnormalities in these structures can lead to cell detachment from the primary tumour and enhance the potential for dissemination and metastatic spread of cancer cells to epithelial characteristics in a process called mesenchymal-to-epithelial transition (ME [72]. Currently, there are some reports proposing an involvement of HOX proteins in EMT process, with an impact on the capacity of invasion and metastasis of cancer cells [ 76]. It has been demonstrated that CDH1 expression is transcriptionally upregulated the direct binding of HOXA5 to their promoter sequence and that the knockdown HOXA5 in mammary cells leads to a loss of epithelial traits, increased stemness and plasticity, and acquisition of more aggressive phenotypes [77].…”