CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16^INK4A

Abstract

C-terminal binding protein-2 (CtBP2), as a transcriptional co-repressor, has been shown to mediate the repression of p16(INK4A) , a tumor suppressor gene product, in primary human cells. Here we aimed to investigate how the correlation between CtBP2 and p16(INK4A) influenced the development of esophageal squamous cell carcinoma (ESCC). Immunohistochemistry of ESCC tissue sections indicated that the CtBP2 and p16(INK4A) expressions were inversely correlated to each other with a linear regression coefficient of -0.747 (P < 0.05), and Western blot analysis revealed that CtBP2 was higher expressed in tumorous tissues than in adjacent non-tumorous tissues. Either CtBP2 or p16(INK4A) expression was significantly related to histological differentiation (P = 0.016 or 0.001) and to the expression of Ki-67, a proliferating marker (P = 0.006 or 0.02), and patients with higher CtBP2 and lower p16(INK4A) expressions had shorter overall survival. We also observed that CtBP2 modulated the cell proliferation and cell cycle in ECA109 cells, an ESCC cell line, by inhibiting p16(INK4A) . Overexpression or knockdown of CtBP2 in ECA109 cells was found to inhibit or activate the mRNA or protein expression of p16(INK4A) , which in turn altered the cell proliferation and cell cycle in ECA109 cells, as measured by flow cytometry and cell count assay. Additionally, after ECA109 cells silenced for CtBP2 were treated with cisplatin (an anti-ESCC agent), the p16(INK4A) expression was up-regulated, and the cell apoptosis was promoted, thus confirming the repression of p16(INK4A) by CtBP2. Collectively, all results suggested that CtBP2 might contribute to the progression of ESCC through a negative transcriptional regulation of p16(INK4A).

C-terminal binding protein-2 promotes cell proliferation and migration in breast cancer via suppression of p16INK4A

“…Collectively, our findings suggest that CtBP2 and p16 INK4A expression is related to the cell cycle. Our results are consistent with a previous study by Guan et al [14]. …”

“…An increasing body of evidence indicates that CtBP2 is involved in tumorigenesis and tumor progression by the regulation of several essential cellular processes, such as transcriptional repression [9], and is correlated with poor prognosis in a number of tumor types [11, 14, 28–31]. CtBP2 works against important tumor suppressors such as E-cadherin [32], p16 INK4A [5], p15 Ink4b , PTEN, HIPK2 [4], Ink4a/Arf [8] and APC [33], and enhances cell proliferation, migration and invasion.…”

“…CtBP2-mediated repression results in the inhibition of p16 INK4A [5], E-cadherin [6], PTEN [7, 8] and PERP (p53-effector related to pmp-22) [4] leading to the oncogenesis [9]. Clinically, the expression of CtBP2 is increased in patients with malignant cancers [10–14], and associated with a poorer prognosis.…”

“…The protein expression of p16 INK4A is reduced in human primary tumors, including those of ESCC (esophageal squamous cell carcinoma) [14], urothelial cancer [20], ovarian cancer [21], non-small cell lung carcinoma, glioma and breast carcinoma [22]. p16 INK4A blocks the cell cycle progression by binding to either CDK4 or CDK6, and inhibiting the action of cyclin D [23–26].…”

C-terminal binding proteins: central players in development and disease

“…Specifically, increased CtBP expression negatively regulates the tumor suppressor p16INK4a and prevents cell senescence in human esophageal squamous cell carcinoma, suggesting that CtBP levels may have a direct role in the evasion of cell cycle regulation in this tumor type (111,112). Moreover, CtBP has been shown to repress expression of p21 (waf1/cip1) in a PARP-dependent manner during DNA damage conditions known to be prevalent in tumor micro-environments (113).…”