PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer

Abstract

Classical Non-homologous End Joining (NHEJ) pathway is the mainstay of cellular response to DNA double strand breaks. While aberrant expression of genes involved in this pathway has been linked with genomic instability and drug resistance in several cancers, limited information is available about its clinical significance in colon cancer. We performed a comprehensive analysis of seven essential genes, including XRCC5, XRCC6, PRKDC, LIG4, XRCC4, NHEJ1, and PAXX of this pathway, in colon cancer using multi-omics datasets, and studied their associations with molecular and clinicopathological features, including age, gender, stage, KRAS mutation, BRAF mutation, microsatellite instability status and promoter DNA methylation in TCGA colon cancer dataset. This analysis revealed upregulation of XRCC5, PRKDC, and PAXX in colon cancer compared to normal colon tissues, while LIG4 and NHEJ1 (XLF) displayed downregulation. The expression of these genes was independent of age and KRAS status, while XRCC5, PRKDC, and LIG4 exhibited reduced expression in BRAF mutant tumors. Interestingly, we observed a strong association between XRCC6, XRCC5, PRKDC and LIG4 overexpression and microsatellite instability status of the tumors. In multivariate analysis, high PAXX expression emerged as an independent prognostic marker for poor overall and disease specific survival. We also observed hypomethylation of PAXX promoter in tumors, which exhibited a strong correlation with its overexpression. Furthermore, PAXX overexpression was also associated with several oncogenic pathways as well as a reduction in numbers of tumor-infiltrating lymphocytes.

Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development

“…Even though the underlying mechanism was not quite known, it was suggested that PAXX may be involved in some proto-carcinoma signaling pathways through its function beyond DNA repair. Meanwhile, there is a correlation between the overexpression of PAXX and the survival rate of patients, and the expression of PAXX may be used as a prognostic marker for disease-specific survival ( 95 ).…”

“…Interestingly, in OS cells that are resistant to doxorubicin or cisplatin, the expression of PAXX was upregulated, and when PAXX was knocked out or specifically inhibited, drug sensitivity was restored. In this scenario, PAXX might be used as a target to effectively promote the effects of chemotherapy drugs ( 95 ). In addition, for tumors with XLF mutations, we could inhibit PAXX,which has less damage to the body after knockdown, as adjuvant therapy.…”

Proteomic Dynamics of Breast Cancers Identifies Potential Therapeutic Protein Targets

“…Their protein complex could bind to DNA and be involved in DNA repair and transcription of selected genes, such as ERBB2 [23]. Similar differences in the correlation of the complex component abundances at protein and transcription level were also apparent in the colon cancer [24]. Therefore, phenotype-related functions may be better reflected at the protein level.…”

C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer

“…[16][17][18] Interestingly, it was recently documented that C9orf142 is highly expressed in colon cancer tissues due to its promoter hypo-methylation and acts as an independent prognosticator in colon cancer. 19 In addition, C9orf142 is up-regulated in chemoresistant osteosarcoma 20 and glioma 21 cells. Interestingly, examination of our recently released TNBC proteomic 22 and transcriptomic 23 datasets reveals that C9orf142 is markedly increased in TNBC tissues and has a positive correlation with lymph node metastasis of TNBC patients.…”

“…Evidence from mouse model studies indicates that C9orf142 is a compensatory factor in the development of central nervous and immune systems, 14,15 and that combined deficiency of C9orf142 and XRCC4‐like factor (XLF) results in embryonic lethality 16‐18 . Interestingly, it was recently documented that C9orf142 is highly expressed in colon cancer tissues due to its promoter hypo‐methylation and acts as an independent prognosticator in colon cancer 19 . In addition, C9orf142 is up‐regulated in chemoresistant osteosarcoma 20 and glioma 21 cells.…”