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Fulltext Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis

Cheng KJ, Mohamed EHM, Syafruddin SE, Ibrahim ZA

J Cell Commun Signal, 2023 Mar;17(1):189-208.
PMID: 35534784 DOI: 10.1007/s12079-022-00681-3

Pathogenic infections have significant roles in the pathogenesis of colorectal cancer (CRC). These infections induce the secretion of various damage-associated molecular patterns (DAMPs) including interleukin-1 alpha (IL-1α) and high mobility group box-1 (HMGB1). Despite their implication in CRC pathogenesis, the mechanism(s) that modulate the secretion of IL-1α and HMGB1, along with their roles in promoting CRC tumourigenesis remain poorly understood. To understand the secretory mechanism, HT-29 and SW480 cells were stimulated with infectious mimetics; polyinosinic:polycytidylic acid [Poly(I:C)], lipopolysaccharide (LPS) and pro-inflammatory stimuli; tumour necrosis factor-alpha (TNF-α). IL-1α and HMGB1 secretion levels upon stimulation were determined via ELISA. Mechanism(s) mediating IL-1α and HMGB1 secretion in CRC cells were characterized using pharmacological inhibitors and CRISPR-Cas9 gene editing targeting relevant pathways. Recombinant IL-1α and HMGB1 were utilized to determine their impact in modulating pro-tumourigenic properties of CRC cells. Pharmacological inhibition showed that Poly(I:C)-induced IL-1α secretion was mediated through endoplasmic reticulum (ER) stress and RIPK1 signalling pathway. The secretion of HMGB1 was RIPK1-dependent but independent of ER stress. RIPK1-targeted CRC cell pools exhibited decreased cell viability upon Poly(I:C) stimulation, suggesting a potential role of RIPK1 in CRC cells survival. IL-1α has both growth-promoting capabilities and stimulates the production of pro-metastatic mediators, while HMGB1 only exhibits the latter; with its redox status having influence. We demonstrated a potential role of RIPK1-dependent signalling pathway in mediating the secretion of IL-1α and HMGB1 in CRC cells, which in turn enhances CRC tumorigenesis. RIPK1, IL-1α and HMGB1 may serve as potential therapeutic targets to mitigate CRC progression.
IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy

Cheng KJ, Mejia Mohammed EH, Khong TL, Mohd Zain S, Thavagnanam S, Ibrahim ZA

Crit Rev Oncol Hematol, 2021 Jul;163:103398.
PMID: 34147647 DOI: 10.1016/j.critrevonc.2021.103398

Inflammation has been well-established as a hallmark of colorectal cancer (CRC). Interleukin-1 alpha (IL-1α) is one of the primary inflammatory mediators driving the pathogenesis of inflammation-associated CRC. This systematic review presents the roles of IL-1α in the pathogenesis of the disease. Bibliographic databases PubMed, Science Direct, Scopus and Web of Science were systematically searched for articles that addresses the relationship between IL-1α and colorectal cancer. We highlighted various mechanisms by which IL-1α promotes the pathogenesis of CRC including enhancement of angiogenesis, metastasis, resistance to therapy, and inhibition of tumour suppressive genes. We also discussed the potential mechanisms by which IL-1α expression is induced or secreted in various studies. Beyond these, the systematic review also highlights several potential therapeutic strategies which should be further explored in the future; to target IL-1α and/or its associated pathways; paving our way in finding effective treatments for CRC patients.
HMGB1: an overview of its versatile roles in the pathogenesis of colorectal cancer

Cheng KJ, Alshawsh MA, Mejia Mohamed EH, Thavagnanam S, Sinniah A, Ibrahim ZA

Cell Oncol (Dordr), 2020 Apr;43(2):177-193.
PMID: 31677065 DOI: 10.1007/s13402-019-00477-5

BACKGROUND: In recent years, the high mobility group box-1 (HMGB1) protein, a damage-associated molecular pattern (DAMP) molecule, has been found to play multifunctional roles in the pathogenesis of colorectal cancer. Although much attention has been given to the diagnostic and prognostic values of HMGB1 in colorectal cancer, the exact functional roles of the protein as well as the mechanistic pathways involved have remained poorly defined. This systematic review aims to discuss what is currently known about the roles of HMGB1 in colorectal cancer development, growth and progression, and to highlight critical areas for future investigations. To achieve this, the bibliographic databases Pubmed, Scopus, Web of Science and ScienceDirect were systematically screened for articles from inception till June 2018, which address associations of HMGB1 with colorectal cancer.
CONCLUSIONS: HMGB1 plays multiple roles in promoting the pathogenesis of colorectal cancer, despite a few contradicting studies. HMGB1 may differentially regulate disease-related processes, depending on the redox status of the protein in colorectal cancer. Binding of HMGB1 to various protein partners may alter the impact of HMGB1 on disease progression. As HMGB1 is heavily implicated in the pathogenesis of colorectal cancer, it is crucial to further improve our understanding of the functional roles of HMGB1 not only in colorectal cancer, but ultimately in all types of cancers.
Insights into the molecular mechanisms and signalling pathways of epithelial to mesenchymal transition (EMT) in colorectal cancer: A systematic review and bioinformatic analysis of gene expression

Azizan S, Cheng KJ, Mejia Mohamed EH, Ibrahim K, Faruqu FN, Vellasamy KM, et al.

Gene, 2024 Feb 20;896:148057.
PMID: 38043836 DOI: 10.1016/j.gene.2023.148057

Colorectal cancer (CRC) is ranked as the second leading cause of mortality worldwide, mainly due to metastasis. Epithelial to mesenchymal transition (EMT) is a complex cellular process that drives CRC metastasis, regulated by changes in EMT-associated gene expression. However, while numerous genes have been identified as EMT regulators through various in vivo and in vitro studies, little is known about the genes that are differentially expressed in CRC tumour tissue and their signalling pathway in regulating EMT. Using an integration of systematic search and bioinformatic analysis, gene expression profiles of CRC tumour tissues were compared to non-tumour adjacent tissues to identify differentially expressed genes (DEGs), followed by performing systematic review on common identified DEGs. Fifty-eight common DEGs were identified from the analysis of 82 tumour tissue samples obtained from four gene expression datasets (NCBI GEO). These DEGS were then systematically searched for their roles in modulating EMT in CRC based on previously published studies. Following this, 10 common DEGs (CXCL1, CXCL8, MMP1, MMP3, MMP7, TACSTD2, VIP, HPGD, ABCG2, CLCA4) were included in this study and subsequently subjected to further bioinformatic analysis. Their roles and functions in modulating EMT in CRC were discussed in this review. This study enhances our understanding of the molecular mechanisms underlying EMT and uncovers potential candidate genes and pathways that could be targeted in CRC.