Overexpression of HOXA1 correlates with poor prognosis in patients with hepatocellular carcinoma

Abstract

HOXA1 overexpression is sufficient for malignant transformation of nontumorigenic epithelial cells. It is known that HOXA1, which was upregulated in squamous cell carcinomas, affects both cell growth and death. The forced expression of HOXA1 in human breast cancer cells results in increased cell growth activity. However, it has not been reported in hepatocellular carcinoma (HCC). In this study, we used immunohistochemistry to compare HOXA1 protein expression in HCC and normal liver tissues and further analyzed HOXA1 protein expression in 156 clinicopathologically characterized HCC cases. We stably knocked down the endogenous expression level of HOXA1 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells, we examined in vitro cell growth by the MTT assay, anchorage-independent growth through a soft agar colony formation assay and cell migration/invasion by transwell and Boyden chamber assay. In addition, we also investigated in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Our results showed that the protein expression level of HOXA1 was markedly higher in HCC tissues than that in normal liver tissue (P = 0.019). In addition, a high expression level of HOXA1 protein was positively correlated with the T classification (P < 0.001), the N classification (P < 0.001), distant metastasis (P = 0.004), and the clinical stage (P < 0.001) of HCC patients. Patients with higher HOXA1 expression showed a significantly shorter overall survival time compared with patients with low HOXA1 expression. Multivariate analysis suggested that HOXA1 expression might be an independent prognostic indicator (P < 0.001) for the survival of patients with HCC. HOXA1-specific shRNA (shHOXA1) successfully knocked down HOXA1 endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHOXA1 cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, and cell migration and invasion (P < 0.05). In vivo, the xenograft transplants from shHOXA1 cells gave rise to much smaller tumors compared with those from shCtrl cells. Collectively, high HOXA1 expression is associated with poor overall survival in patients with HCC. The downregulation of HOXA1 inhibits growth, anchorage-independent growth, and migration and invasion of HepG2 cells.

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells

“…7,[19][20][21][22] However, the role of lncRNA-HOTAIR in the chemoresistance of SCLC remains unknown. In this study, we initially identified lncRNA-HOTAIR as a regulator in chemoresistance of SCLC by qRT-PCR in H69/H69AR and H446/H446AR cells.…”

Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells

“…Loss-of-function and lineage studies have implicated Hoxa1 in development of the inner ear, heart, neural crest specification, and hindbrain patterning (31)(32)(33). Growing evidence suggests roles for Hoxa1 in etiology of various cancers through modulation of cell proliferation, invasion, and metastasis (34)(35)(36)(37). These diverse functional roles for Hoxa1 appear to be at least partially related to its ability to influence key signaling pathways in differentiating cells (35).…”

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

“…Previous studies have suggested that HOXA1 is overexpressed in various cancers, including breast, liver, oral and lung cancer (Chariot et al, 1996;Abe et al, 2006;Bitu et al, 2012;Zha et al, 2012). The forced expression of HOXA1 promoted oncogenic transformation by modulating the p44/42 MAP kinase pathway and bcl-2 in MCF-10 cells (Mohankumar et al, 2007).…”