HOXA13 Promotes Cancer Cell Growth and Predicts Poor Survival of Patients with Esophageal Squamous Cell Carcinoma

Abstract

Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. Here, we investigated whether inhibition of HOXA13, a member of the homeobox genes, was sufficient to affect the proliferation of esophageal cancer cells in vitro and in vivo, and studied the association between HOXA13 expression and survival of patients with esophageal squamous cell carcinoma (ESCC). HOXA13 expression was permanently knocked down using an RNA interference technique, and cell strain with stable knockdown of HOXA13 protein was established. Colony formation assay showed that the number of colonies in HOXA13 protein-deficient cells was significantly less than that of control cells (P < 0.01). Tumor growth in nude mice showed that the weight and volume of tumors from the HOXA13 knockdown cells was significantly less than that from the control cells (P < 0.01). Then, HOXA13 expression in ESCC specimens and paired noncancerous mucosa was detected by immunohistochemistry, and overexpression of HOXA13 was found to be more pronounced in ESCCs than paired noncancerous mucosa (P < 0.05). Furthermore, the association of HOXA13 expression and disease-free survival time was analyzed in 155 ESCC cases. The median survival time of patients expressing HOXA13 was significantly shorter than HOXA13-negative patients (P = 0.0006). Multivariate analysis indicated that tumor-node-metastasis (TNM) stage and HOXA13 expression were independent predictors of disease-free survival time of patients with ESCC. Our results showed that HOXA13 expression enhanced tumor growth in vitro and in vivo, and was a negative independent predictor of disease-free survival of patients with ESCC. [Cancer Res 2009;69(12):4969-73]

Overexpression of HOXA13 as a Potential Marker for Diagnosis and Poor Prognosis of Hepatocellular Carcinoma

“…As a transcription factor, immunohistochemical labeling for HOXA13 is expected to localize in nuclei of HCC cells, as previously reported (Knosp et al 2004;Cillo et al 2011). However, Gu et al (2009) also found cytoplasmic localization of HOXA13 in esophageal squamous cell carcinoma and this phenomenon was also found in many other transcription factors (Sun et al 2013). The regulation of transcription factor activity plays an important role in many biological processes.…”

“…Available evidence indicates that HOXA13 plays a prominent role in tumor survival and progression (Gu et al 2009;Cillo et al 2011). In embryonic development, each HOX gene is expressed in a spatiotemporal pattern, and thus HOXA13 is expressed specifically in the cloacal mesoderm and hindgut, but not in liver Roberts et al 1995;Takahashi et al 2004).…”

“…Mechanisms known to influence transcription factor activity include post-translational modification, expression levels, protein stability, and subcellular localization. It is speculated that the cytoplasmic localization may be due to a modulation of nuclear localization signals with nuclear export and interaction with a cytoplasmic anchoring factor (Ziegelbauer et al 2001;Haller et al 2004;Stevens and Mann 2007;Gu et al 2009).…”

The HOX gene network in hepatocellular carcinoma

“…18,19 Here, we show that HCC selection on the basis of HOXA13 hyperexpression correlates, at transcriptome level, with the identification of expression gene profiles characteristic of liver development/cell cycle/nuclear pore related HCC phenotypes displaying poor prognosis.…”

HOXB7 Predicts Poor Clinical Outcome in Patients with Advanced Esophageal Squamous Cell Cancer

“…The expression of HOX genes keeps to temporal and spatial colinearity in embryonic development (Shah and Sukumar, 2010). Aberrant expression of HOX genes was found in various types of cancer, such as ovarian cancer (Yamashita et al, 2006), leukemia (Chang et al, 1997), breast cancer (Jin et al, 2012), cervical cancer (How et al, 2013), prostate cancer (Rubin et al, 2007), melanoma (Care et al, 1996), oral squamous cell cancer (De Souza Setubal Destro et al, 2010) and esophageal squamous cell cancer (Gu et al, 2009). However, the detailed relationship between HOX genes and tumorigenesis remains unclear (Shah and Sukumar, 2010).…”