A correlation between BCL-2 modifying factor, p53 and livin gene expressions in cancer colon patients

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Abstract

Accumulating evidence has revealed that livin gene and BCL-2 modifying factor (BMF) gene are closely associated with the initiation and progression of colon carcinoma by activating or suppressing multiple malignant processes. Those genes that can detect colon - cancer are a promising approach for cancer screening and diagnosis. This study aimed to evaluate correlation between livin, BMF and p53 genes expression in colon cancer tissues of patients included in the study, and their relationship with clinicopathological features and survival outcome in those patients. In this study, 50 pathologically diagnosed early cancer colon patients included and their tissue biopsy with 50 matched adjacent normal tissue, and 50 adenoma tissue specimens were analyzed for livin gene and BMF gene expressions using real time PCR. The relationship of those genes expressions with clinicopathological features, tumor markers, Time to Progression and overall survival for those patients were correlated in cancer colon group. In this study, there was a significant a reciprocal relationship between over expression of livin gene and down regulation of BMF and p53 genes in colon cancer cells. Livin mRNA was significantly higher, while BMF and p53 mRNA were significantly lower in colorectal cancer tissue compared to benign and normal colon tissue specimens (P < 0.001), however, this finding was absent between colon adenomas and normal mucosa. There was a significant association between up regulation of livin and down regulation of BMF and p53 expressions with more aggressive tumor (advanced TNM stage), rapid progression with metastasis and decreased overall survival in cancer colon patients, hence these genes can serve as significant prognostic markers of poor outcome in colon cancer patients. This work highlights the role of livin, BMF and p53 genes in colorectal tumorigenesis and the applicability of using those genes as a diagnostic and prognostic markers in patients with colon carcinoma and as a good target for cancer colon treatment in the future.

Highlights

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Apoptosis and anti-apoptotic markers are a hallmark in cancer.
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There is a reciprocal relation between anti-apoptotic livin and proapoptotic BMF and P53 genes expression.
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Upregulation of livin and downregulation of BMF and P 53 genes expression are markers of poor prognosis in colon cancer.
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High livin expression is associated with more aggressive tumors with rapid progressions and metastasis.

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Targeting BCL-2 regulated apoptosis in cancer

Kirsteen J. Campbell, Stephen Tait (2018)

The ability of a cell to undergo mitochondrial apoptosis is governed by pro- and anti-apoptotic members of the BCL-2 protein family. The equilibrium of pro- versus anti-apoptotic BCL-2 proteins ensures appropriate regulation of programmed cell death during development and maintains organismal health. When unbalanced, the BCL-2 family can act as a barrier to apoptosis and facilitate tumour development and resistance to cancer therapy. Here we discuss the BCL-2 family, their deregulation in cancer and recent pharmaceutical developments to target specific members of this family as cancer therapy.

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Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Simon Walker, Ian Brown, Vicki LJ Whitehall … (2013)

Approximately 30% of colorectal carcinomas develop via a serrated neoplasia pathway, named for the pattern of crypts in the precursor polyps. Molecular abnormalities consistently involve methylation of CpG islands [CpG island methylator phenotype (CIMP)] of low degree (CIMP-L) or high degree (CIMP-H), and activating mutations of the mitogen-activated protein kinase pathway components BRAF or KRAS. Microsatellite instability (MSI) of a high level (MSI-H) is often present, allowing for a molecular classification of serrated pathway carcinoma as: (i) BRAF mutant/CIMP-H with either a) MSI-H or b) microsatellite stable (MSS); and (ii) KRAS mutant/CIMP-L/MSS. Precursor polyps include sessile serrated adenoma (SSA), characterized by proximal location, crypt architectural disturbance, and BRAF mutation. Microvesicular hyperplasic polyp (MVHP) probably precedes the development of SSA, and borderline lesions between MVHP and SSA occur. Cytological dysplasia in SSA portends advanced genetic abnormality and a high risk of progression to carcinoma. The traditional serrated adenoma has a predilection for the left colon, tubulovillous architecture, eosinophilic cytoplasm, and frequent KRAS mutation. Serrated morphology carcinoma is a new World Health Organization subtype with well-differentiated, mucinous or trabecular patterns. It has frequent KRAS or BRAF mutations and a poor prognosis. This review provides an insight into the histology and molecular mechanisms driving these serrated pathway lesions. © 2012 Blackwell Publishing Ltd.

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Author and article information

Contributors

Eman AE. Badr

Journal

Journal ID (nlm-ta): Biochem Biophys Rep

Journal ID (iso-abbrev): Biochem Biophys Rep

Title: Biochemistry and Biophysics Reports

Publisher: Elsevier

ISSN (Electronic): 2405-5808

Publication date PMC-release: 09 February 2020

Publication date Collection: July 2020

Publication date (Electronic): 09 February 2020

Volume: 22

Electronic Location Identifier: 100747

Affiliations

[a ]Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine – Menoufia University, Egypt

[b ]Biochemistry Division of Chemistry Department, Faculty of Science – Menoufia University, Egypt

[c ]Department of Organic Chemistry, Faculty of Science – Menoufia University, Egypt

[d ]Department of Medical Microbiology and Immunology, Faculty of Medicine – Menoufia University, Egypt

[e ]Clinical Oncology Department, Faculty of Medicine, Menoufia University, Egypt

Author notes

[∗ ]Corresponding author. Professor of Medical Biochemistry and Molecular Biology, Faculty of Medicine- Menoufia University, Shebin Elkom city, 32511, Egypt. ebadr2014@ 123456gmail.com

Article

Publisher ID: S2405-5808(19)30381-4 Publisher ID: 100747

DOI: 10.1016/j.bbrep.2020.100747

PMC ID: 7013244

PubMed ID: 32072027

SO-VID: 687d19ca-e044-46fa-a17d-35899db3cf00

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 20 December 2019

Date revision received : 1 February 2020

Date accepted : 3 February 2020

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