HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Abstract

HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer

“…In cell-based experiments, HOTAIR promoted breast cancer cell invasion by recruiting PRC2 to specific targets genes, leading to H3K27 trimethylation and epigenetic silencing of suppressor genes [3]. Another study showed that upregulation of HOTAIR enhanced the resistance of breast cancer cells to radiotherapy by downregulating the expression of homeobox D10 (HOXD10), an mRNA encoding a transcriptional repressor that inhibits the expression of cell migration and invasion-associated genes [62]. Thus, HOTAIR can be regarded as a valid therapeutic target for the reversal of radiotherapy resistance in patients with breast cancer [63].…”

DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C

“…HOXD10, by contrast, has been found to exert anti-angiogenic activity, and inhibited migration and sprouting when overexpressed in venous endothelial cells (Myers et al, 2002). In addition, both negative and positive roles for HOXD10 in (tumor) cell proliferation, migration, and invasiveness have been reported, depending on the specific cell line analyzed (Cho et al, 2008;Hakami et al, 2014;Sharpe et al, 2014;Yang et al, 2015;Zha et al, 2012). Taken together, this indicates that HOXD10 exerts different functional roles in different cell types.…”

MiR‑381 regulates cell motility, growth and colony formation through PIK3CA in endometriosis‑associated clear cell and endometrioid ovarian cancer

“…HOXD10 drives increased transcription of miR-381, perhaps leading to the downregulation of PIK3CA. Previous work has demonstrated that HOXD10 is frequently downregulated in other cancer types, including breast cancer (38), ovarian cancer (24), bladder cancer (39) and cholangiocellular carcinoma (40). Ectopic expression of HOXD10 significantly blocks tumor cell migration and invasiveness, indicating that HOXD10 may serve as a tumor suppressor (38,41).…”