Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown.
Ectopic expression of CACNA2D3 inhibited cell proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas CACNA2D3 depletion inhibited cell viability and invasion.
Our study also warrants further exploration in the potential therapeutic use of existing epigenetic targeting drugs (e.g., 5-azacytidine, SAHA) to reconstitute CACNA2D3-associated tumor suppression in NPC.
Inverse effects were seen by CACNA2D3 small interfering RNA treatment in the CACNA2D3-positive cell lines, indicating that CACNA2D3 may have tumor suppressive functions.
Ectopic expression of CACNA2D3 inhibited cell proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas CACNA2D3 depletion inhibited cell viability and invasion.
Our findings show that CACNA2D3-mediated increase in intracellular calcium (Ca2+) can induce mitochondrial-mediated apoptosis and activation of NLK (through the Wnt/Ca2+ pathway) to antagonize Wnt signaling-mediated anchorage-dependent and independent cell proliferation (via CCND1 and CMYC), invasion (via MMP7) and epithelial-to-mesynchemal transition (via SNAIL).
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).
Mutation analysis of nine genes located in 3p21.1-p14.3, including CACNA2D3, which is directly disrupted by one breakpoint of the t(3;17), identified no pathogenic mutation in eight sporadic patients with ZLS.
These data suggest that the gene responsible for ZLS is located in 3p14.3 and implicates four likely candidate genes in this region: CACNA2D3, encoding a voltage-dependent calcium channel, LRTM1, a gene of unknown function embedded within CACNA2D3, WNT5A, encoding a secreted signaling protein of the WNT family, and ERC2, which codes for a synapse protein.