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

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-...

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Published in:	PloS one Vol. 16; no. 1; p. e0245581
Main Authors:	Faruk, Mohammed, Ibrahim, Sani, Aminu, Surajo Mohammed, Adamu, Ahmed, Abdullahi, Adamu, Suleiman, Aishatu Maude, Rafindadi, Abdulmumini Hassan, Mohammed, Abdullahi, Iliyasu, Yawale, Idoko, John, Saidu, Rakiya, Randawa, Abdullahi Jibril, Musa, Halimatu Sadiya, Ntekim, Atara, Shah, Khalid Zahir, Abubakar, Sani, Adoke, Kasimu Umar, Manko, Muhammad, Awasum, Cheh Agustin
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-01-2021 Public Library of Science (PLoS)
Subjects:	Annexin V Apoptosis Apoptotic proteins Aspirin BAX protein Bcl-2 protein Bcl-x protein Biochemistry Biology and Life Sciences Blood Blood transfusion Blood transfusions Cancer Cancer therapies Caspase-3 Cell activation Cell growth Cell migration Chemokine receptors Chemokines Chemotherapy Colorectal cancer Colorectal carcinoma Cytochrome Dendritic cells Deoxyribonucleic acid DIABLO protein DNA DNA damage DNA repair Drug therapy Editing Fluorouracil Gynecology Health aspects Health care facilities Hematology Histidine Immune system Immunosurveillance Medical prognosis Medical research Medicine Medicine and Health Sciences Metabolism Metastasis Methodology Mitochondria Mortality MSH2 protein Obstetrics Oncology, Experimental p53 Protein Pathology Patient outcomes PD-L1 protein Physical Sciences Prognosis Proteins Radiation Radiation therapy Radiology Research and Analysis Methods Reviews Surgery Teaching hospitals Transfusion Tumor cells Zinc Zinc finger proteins Nigeria Africa
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0245581