The Gap Junction Protein Cx31.1 Role In The Proliferation And Metastasis Of Lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide. Despite intense efforts to improve lung cancer treatment, the overall 5-year survival remains approximately 10% to 15%. According to histological type, there are two most prevalent histological types of lung carcinoma:non-small-cell lung cancer (NSCLC) and small-cell lung carcinoma, and the most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Approximately 85% of all lung cancer cases are categorized as non-small cell lung cancer, and most patients present with advanced disease at the time of diagnosis. NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. Therefore, development of innovative, effective targets and new target-based therapies is of prime importance.Gap junctions are channels that link the cytoplasm of adjacent cells. Gap junctional intercellular communication (GJIC) established by these channels allows for the passage of small molecules of<1,000 Da, such as ions and secondary messenger molecules. Gap junctions play important roles in various physiologic functions such as regulation of cell proliferation, cell differentiation, tissue development, and cell apoptosis. Gap junctions are made of two hemi-channels, called connexons, which are composed of six molecules of the membrane spanning connexin protein. There are more than 21 connexin (Cx) genes in the human genome. In most cases, connexins act as tumor suppressors. Greatly reduced or absence of connexin expression or GJIC have been found in various cancers, such as lung cancer.Connexin31.1, also known as gap junction protein B5 (GJB5), a 273 amino acid peptide with a molecular mass of 31.088 kD, is predominantly expressed in the testes and the skin epidermis. Connexin31.1 rarely forms functional gap junction channels, either with itself or with other connexin isoforms. A large number of studies have been performed on members of the connexin family, such as Cx43, Cx32 and Cx26. However, there was relatively little work focusing on Cx31.1.The present study was conducted to investigate the effect of Cx31.1 on non-small cell lung cancer (NSCLC). We found that the Cx31.1 was downregulated in NSCLC cell lines, and the expression levels were reversely related with their metastatic potential. We ectopically expressed Cx31.1 in H1299 NSCLC cell line to examine the influence of Cx31.1 overexpression. The results showed that overexpression of Cx31.1 in H1299 cells reduced cell proliferation, induced a delay in the G1 phase, inhibited anchorage-independent growth, and suppressed cell migration and invasion. The cell cycle delay and cell migration and invasion suppressive effects of Cx31.1 were partially reversed by siRNA targeting mRNA of Cx31.1. Moreover, xenografts of Cx31.1 overexpressing H1299 cells showed reduced tumorigenicity. These results suggested that Cx31.1 has tumor-suppressive properties. Further investigation indicated that cyclin D3 may be responsible for Cx31.1 induced G1 phase delay. Importantly, Cx31.1 increased the expression of epithelial markers, such as cytokeratin 18, and decreased expression of mesenchymal markers, such as vimentin, indicating a Cx31.1-mediated partial shift from a mesenchymal towards an epithelial phenotype.We concluded that Cx31.1 inhibit the malignant properties of NSCLC cell lines, the mechanisms under this may include regulation of EMT. UV-related DNA damage are repaired via the nucleotide excision repair pathway. NER may be subdivided into transcription-coupled repair and global genome repair, and the xeroderma pigmentosum group C (XPC) protein is specific to this latter repair pathway recognizing helix distorting lesions and initiating their repair. Inactivating XPC mutations are associated with an extremely high risk of cancer. Polymorphisms (A33512C, C21151T and PAT-/+) of XPC were shown to contribute to genetic susceptibility to cancer, as well as lung cancer. However, association studies on these polymorphisms in cancer have shown conflicting results. Thus, we performed a meta-analysis.Our meta-analysis investigated the associations between the three XPC polymorphisms and cancer risk with a total of 12,408 cancer patients and 14,984 controls from 32 case-control studies, of which 6 studies with 2,471 patients and 2,479 controls were about lung cancer.Overall, there was no significant associations between 33512C (9,091 patients and 11,553 controls) and cancer risk. No significant association was found in stratification analysis by tumor sites and ethnicities except that an elevated lung cancer risk under recessive genetic model in all subjects (P=0.04, OR=1.20,95% CI 1.00-1.45,.Pheterogeneity=0.88) was found. There was no significant association between 21151T (5,227 patients and 5,959 controls) and cancer risk in all subjects. However, The Caucasians of XPC 21151TT genotype have a high susceptibility compared with that of other genotypes (recessive genetic model, P=0.006, OR=1.45,95% CI 1.11-1.90,Pbeterogeneity=0.75; additive genetic model, P=0.02, OR=1.41,95% CI 1.07-1.81,Pheterogeneity=0.41).2115IT might increase bladder cancer risk under recessive genetic model (P=0.02, OR=1.49,95% CI 1.06-2.09,Pheterogeneity=0.47) and additive genetic model (P=0.02, OR=1.49,95% CI 1.05-2.11, Pheterogeneity=0.23). There was no significant association between PAT+(4,600 patients and 4,866 controls) and cancer risk in all subjects. An increased cancer risk in Caucasians was found under recessive genetic model (P=0.02, OR=1.20,95% CI 1.03-1.40, Pheterogeneity=0.37) and additive genetic model (P=0.008, OR=1.26,95% CI 1.06-1.50, Pheterogeneity=0.13). XPC PAT+allele might increase head and neck cancer risk (P=0.02, OR=1.29,95% CI 1.04-1.59,Pheterogeneity=0.15). The present results suggested association only in particular tumor sites, and polymorphisms of XPC seems have more significant influence on tumor susceptibility of Caucasians. It seems that homozygote of mutant alleles elevated cancer risk more significant.More studies based on larger, stratified case-control population, especially studies investigate the combined effect of XPC A33512C, C21151T and PAT should be required to further evaluate the role of these polymorphisms in different cancers.