Senescence, a double-edged sword in cancer biology, With focused on the role of BIRC۵ in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the primary subtype of liver cancer, accounting for ~۹۰% of all cases; HCC is associated with high rates of tumor recurrence and metastasis after primary hepatic resection. Cellular senescence is a state of stable cell cycle arrest characterized by changes in morphology, macromolecule compositions, and the acquisition of pro-inflammatory phenotypes. Senescent cancer cells acquire pro-tumorigenic properties through activation of the senescence-associated secretory phenotype (SASP), which can modulate the tumor microenvironment and increase cancer stemness, invasion, migration and angiogenesis. The present study aimed to identify differentially expressed genes (DEGs) between tumor and normal tissues from HCC samples and compare with senescence-associated genes to find hub genes that have involved in both hepatocarcinogenesis and senescence. Raw microarray data of GSE۶۰۵۰۲, GSE۱۱۲۷۹۰ and GSE۱۴۵۲۰ were obtained from the GEO database. DEGs were obtained using R packages and screened out according to adjusted P-value < ۰.۰۵ and -logFC- ≥۱. Senescence-associated genes file was taken from Cellage database. First, common genes between the senescence-associated genes and DEGs were collected. Then, the hub genes were identified; these genes have function in cancer and also in senescence. The expression patterns were obtained from GEPIA and UALCAN databases and the expression patterns of normal tissue was obtained from HUMAN PROTEIN ATLAS (HPA) and Gtex databases. Among these genes, we focused on BIRC۵ because of its expression pattern and level of expression in normal liver; BIRC۵ (Survivin) is the smallest member of the family of inhibitor of apoptosis protein (IAPs) and is highly expressed in precancerous liver lesions and in malignant HCC cells. BIRC۵ is almost entirely absent in adult tissue, but its upregulation is linked to poor survival in numerous solid tumors. The prognostic role of BIRC۵ gene in HCC has been confirmed across ۱۴ different studies involving ۸۹۰ patients. Also, genetic deletion of BIRC۵ leads to mitotic defect and senescence in HCCs, which then caused inflammation and TNFα induction. In conclusion, targeting BIRC۵ could be a potential therapeutic approach for HCC treatment.

کلیدواژه ها:

liver cancer ، aging ، biomarker discovery ، Survivin ، bioinformatics