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Updated: May 12, 2026
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Investigation of tumor suppressing function of CACNA2D3 in esophageal squamous cell carcinoma
Yan Li1, Cai-Lei Zhu, Chang-Jun Nie
1State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China. liy6@mail.sysu.edu.cn
Background:
Deletion 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.
Methods:
Expression 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 Ca(2+) 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.
Insights
CACNA2D3 is a tumor suppressor gene frequently lost in esophageal squamous cell carcinoma (ESCC). Its loss promotes ESCC development and progression by affecting cell cycle and apoptosis.
Area of Science:
- Oncology
- Cancer Genetics
Background:
- 3p deletions are common in esophageal squamous cell carcinoma (ESCC), indicating potential tumor suppressor genes (TSGs).
- CACNA2D3 at 3p21.1 is identified as a potential TSG within these deleted regions.
Purpose of the Study:
- To characterize the role of CACNA2D3 as a tumor suppressor gene in ESCC.
- To investigate the mechanisms underlying CACNA2D3 downregulation and its functional impact on ESCC development.
Main Methods:
- Quantitative real-time PCR and tissue microarray were used to assess CACNA2D3 expression in ESCC.
- Methylation-specific PCR (MS-PCR) investigated the mechanism of CACNA2D3 downregulation.
- In vitro and in vivo assays evaluated the tumor suppressive function, including cell migration and invasion.
Main Results:
- CACNA2D3 was frequently downregulated (50% in initial cohort, 56.7% in tissue microarray) in ESCC, associated with promoter methylation and allele loss.
- Downregulation correlated significantly with lymph node metastasis, advanced TNM stage, and poor patient outcomes.
- Functional studies showed CACNA2D3 inhibits tumorigenicity, cell motility, and induces apoptosis by regulating cell cycle (p21, p53, CDK2) and intracellular calcium levels.
Conclusions:
- CACNA2D3 acts as a novel tumor suppressor gene in ESCC, linked to 3p21 deletions.
- It plays a critical role in suppressing the development and progression of esophageal squamous cell carcinoma.
