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.
Highlights
Esophageal cancer is the sixth most common cancer in the world
We introduced plasmids expressing shRNA targeting three different regions of HOXA13 into EC-109 cells to knock down the expression of HOXA13 protein
Genes regulating normal cell proliferation and differentiation participate in tumorigenesis and/or tumor progression because of their deregulated function or interaction with deregulated target genes
Summary
The majority of esophageal squamous cell carcinoma (ESCC) cases occur in Asia, especially in north central China. Tremendous advances in diagnosis and treatment have been achieved recently; the survival rate has not been significantly improved. Among the reasons are the advanced stage at diagnosis and the lack of an efficacious system both in understanding its carcinogenic mechanism and clinical evaluation, especially the lack of sensitive and specific molecular markers for early detection. Homeobox genes represent classic examples of the intimate relationship between embryogenesis and tumorigenesis. The mammalian HOX genes, which are arranged in clusters (HOXA through HOXD) on four separate chromosomes, encode a subset of transcription factors which regulate axial regional specification during embryonic development and have recently been shown to be aberrantly expressed in a variety of solid tumors [3,4,5]
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