Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases

Abstract

Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host’s protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.

Overexpression of microRNA‐98 inhibits cell proliferation and promotes cell apoptosis via claudin‐1 in human colorectal carcinoma

“…A lower miR-98 expression in glioma cell lines and related tissues was observed and its upregulation can promote glioma cell apoptosis and inhibit the Bcl-2 expression. 32 PCNA is a kind of much conserved protein in archaebacteria as well as several eukaryotic species, of which the decrease marks many proliferative diseases for PCNA which is a general proliferative marker with no discrepancies of gender or age. 28 Hu et al 8 have reported that miR-98 can decrease Bcl-2 and upregulate Bax by targeting MAPK6 in human vascular endothelial cells.…”

Butyrate Inhibits Deoxycholic‐Acid‐Resistant Colonic Cell Proliferation via Cell Cycle Arrest and Apoptosis: A Potential Pathway Linking Dietary Fiber to Cancer Prevention

“…[ 37 ] Proto‐oncogene c‐Myc is a central regulator of cellular proliferation, and plays a key role in cell cycle progression, apoptosis, and cellular transformation. [ 38,39 ] The downregulation of c‐Myc is necessary for cell cycle arrest. [ 38 ] Thus, we examined the effect of butyrate on c‐Myc expression and found that butyrate greatly reduced c‐Myc protein levels in both DCA‐RCL and HCT‐116 cells (Figure 6).…”

“…[ 38,39 ] The downregulation of c‐Myc is necessary for cell cycle arrest. [ 38 ] Thus, we examined the effect of butyrate on c‐Myc expression and found that butyrate greatly reduced c‐Myc protein levels in both DCA‐RCL and HCT‐116 cells (Figure 6). This finding is consistent with that cell cycle progression from the G0/G1 into the S phase is tightly controlled by c‐Myc by regulating the expression of cyclins, cyclin dependent kinases.…”

Prognostic effect of inflammatory genes on stage I-III colorectal cancer – integrative analysis of TCGA data

“…MYC is well known for the role in the progression of CRC [43]. MYC is frequently deregulated in inflammation and the expression is affected by DNA-methylation [11]. PPARGC1A encodes a transcriptional coactivator that regulates the genes involved in energy metabolism [29].…”

“…Inflammatory biomarkers such as NLR, LMR and PLR have been suggested as prognostic markers in colorectal cancer [7][8][9][10]. Chronic inflammation can trigger genetic mutations and epigenetic alternations that promote malignant cell transformation [11]. However, the inflammatory interactions with colon involve various modes of action such as immune cells, cytokines, and other immune mediators in virtually all sequence of CRC progression, including initiation, progression, and metastasis [12].…”