Prognostic significance of BIRC7/Livin, Bcl-2, p53, Annexin V, PD-L1, DARC, MSH2 and PMS2 in colorectal cancer treated with FOLFOX chemotherapy with or without aspirin

Abstract

Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment in vivo in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7/Livin post-FOLFOX treatment compared with pre-treatment (p = 0.0001). This increase provides new insights into the prognostic role of BIRC7/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p < 0.05). Importantly, we found a significant reduction in expression of BIRC7/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments in vivo (p <0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.

Combined time-restricted feeding and cisplatin enhance the anti-tumor effects in cisplatin-resistant and -sensitive lung cancer cells

“…Cisplatin exerted anticancer activity via multiple mechanisms but its most acceptable mechanism involved in generation of DNA lesions by interacting with purine bases on DNA followed by activation of several signal transduction pathways, which finally lead to apoptosis [ 17 ]. However, cancer cells could develop its own specific strategies to evade apoptosis, which facilitated their survival and promoted resistance to anti-cancer therapies [ 32 ], but combined treatment strategies were widely applied to sensitize the anti-cancer therapies in part by preventing the evasion of apoptotic effects [ 33 ]. The presence of galangin enhanced DDP-induced apoptosis by inhibiting Bcl-2 in DDP-resistant lung cancer cells [ 34 ].…”

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

“…BIRC7/Livin is an inhibitor of apoptosis protein (IAP) associated with suppression of apoptosis in CRC [56]. Faruk et al recently explored the expression of proteins relevant for apoptosis including p53, BCL2, Livin and Annexin V in mucinous and non-mucinous CRC [57]. Tumor samples from 23 patients with mucinous CRC were compared with 69 non-mucinous CRCs with neoadjuvant FOLFOX chemotherapy administered in a subset of the cohort.…”

Evaluation of P53 gene expression by immunohistochemistry to diagnosis oral precancerous lesions

“…In some studies, a positive correlation has been found between P53 expression and tumor invasion to surrounding tissues, resulting in tumor stage and prognosis in cancer patients. But other studies have not proven this theory (33)(34)(35)(36)(37)(38)(39). The present study showed that the evaluation of P53 gene expression was well able to detect oral precancerous lesions and their severity by increasing their expression rate.…”