Investigation of Tumor Suppressing Function of CACNA2D3 in Esophageal Squamous Cell Carcinoma

Abstract

BackgroundDeletion of 3p is one of the most frequent genetic alterations in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes (TSGs) within these regions. In this study, one TSG, CACNA2D3 at 3p21.1, was characterized.MethodsExpression of CACNA2D3 in ESCCs was tested by quantitative real-time PCR and tissue microarray. The mechanism of CACNA2D3 downregulation was investigated by methylation-specific polymerase chain reaction (MS-PCR). The tumor suppressive function of CACNA2D3 was characterized by both in vitro and in vivo tumorigenic assays, cell migration and invasion assays.Results CACNA2D3 was frequently downregulated in ESCCs (24/48, 50%), which was significantly associated with promoter methylation and allele loss (P<0.05). Tissue microarray result showed that downregulation of CACNA2D3 was detected in (127/224, 56.7%) ESCCs, which was significantly associated with lymph node metastasis (P = 0.01), TNM staging (P = 0.003) and poor outcome of ESCC patients (P<0.05). Functional studies demonstrated that CACNA2D3 could inhibit tumorigenicity, cell motility and induce apoptosis. Mechanism study found that CACNA2D3 could arrest cell cycle at G1/S checkpoint by increasing expressions of p21 and p53 and decreasing expression of CDK2. In addition, CACNA2D3 could upregulate intracellular free cytosolic Ca2+ and subsequently induce apoptosis.Conclusion CACNA2D3 is a novel TSG responsible to the 3p21 deletion event and plays a critical suppressing role in the development and progression of ESCC.

C2ORF40suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes

“…Silencing C2ORF40 expression promoted breast cancer cell proliferation, migration and invasion. These are consistent with the findings by Li et al 9,11 that upregulation of C2ORF40 inhibits cell proliferation and invasiveness in ESCC and our bioinformatics analysis of clinical information of breast cancer patients. Our data provided the first biological evidence that C2ORF40 may serve as a tumor suppressor in breast cancers.…”

Activating Transcription Factor 4 Promotes Esophageal Squamous Cell Carcinoma Invasion and Metastasis in Mice and Is Associated with Poor Prognosis in Human Patients

“…Therefore, it is crucial to identify tumor molecular markers that are predictive of survival and metastasis and can identify ESCC patients who may benefit from surgical resection. Recently, several genes that are associated with ESCC metastasis have been identified, including Gadd45G [10], glioma-associated oncogene homolog 1 [11], lysine-specific demethylase 1 [12], maspin [13], PLCE1 [14], and CACNA2D3 [15]. These studies have indicated that specific genes may contribute to the metastasis of ESCC.…”

Soluble purified recombinant C2ORF40 protein inhibits tumor cell growth in vivo by decreasing telomerase activity in esophageal squamous cell carcinoma

“…In addition, C2ORF40 has been demonstrated to be chemosensitive to 5-fluorouracil and cisplatin (23,24). Previous research by the present authors demonstrated that C2ORF40 is a candidate tumor suppressor gene and an independent prognostic factor in ESCC, and C2ORF40 gene overexpression inhibits tumor cell proliferation and invasion in ESCC (25)(26)(27)(28)(29). Notably, additional bioinformatics analysis indicated that pro-C2ORF40 protein was a secreted protein with a signal peptide.…”