Fibrotic Phenotype of Peritumour Mesenteric Adipose Tissue in Human Colon Cancer: A Potential Hallmark of Metastatic Properties

The impact of tumour associated stroma on cancer metastasis is an emerging field. However, cancer associated genes in peritumoral adipose tissue (pAT) in human colon cancer have not been explored. The aim of this study was to identify differentially expressed genes (DEGs) associated with cancer pathways in mesenteric pAT compared with adjacent adipose tissue. In total, nine patients with colon cancer pathological stage T2/T4 were employed in this study. DEGs were identified in 6 patients employing Nanostring PanCancer Pathway Panel and pathway enrichment analyses were performed. Differential expression of the 5 most up-regulated and 2 down regulated genes was validated with qRT-PCR. Results showed collagen type I alpha 1 chain (COL1A1) p = 0.007; secreted frizzled related protein (SFRP2) p = 0.057; fibroblast growth factor 7 (FGF7) not significant (ns); phospholipase A2, group IIA (PLA2G2A) ns; nerve growth factor receptor (NGFR) ns; lymphoid enhancer binding factor 1 (LEF1) p = 0.03; cadherin 1, Type 1, E-cadherin (epithelial) (CDH1) 0.09. Results have highlighted down-regulation of the Wingless/Integrated (Wnt) pathway in mesenteric pAT compared to distal adipose tissue. Highly upregulated genes in mesenteric pAT were involved in extracellular matrix (ECM)-receptor interactions and focal adhesion. Highly down regulated genes were involved in the cell cycle. Immunohistochemistry revealed differential distribution of COL1A1 showing maximum levels in tumour tissue and gradually decreasing in distant adipose tissue. COL1A1 and down regulation of Wnt pathway may have a role in local invasion and distant metastasis. COL1A1 may represent a stromal prognostic biomarker and therapeutic target in colon cancer.

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Leptin is a growth factor for human colon cancer cells

Gastroenterology ◽

10.1016/s0016-5085(01)82447-1 ◽

2001 ◽

Vol 120 (5) ◽

pp. A493-A493

Author(s):

J HARDWICK ◽

G VANDENBRINK ◽

S VANDEVENTER ◽

M PEPPELENBOSCH

Keyword(s):

Colon Cancer ◽

Growth Factor ◽

Cancer Cells ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Human Colon Cancer Cells

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Insulin-like growth factor 1 activates methionine adenosyltransferase 2A transcription by multiple pathways in human colon cancer cells

Biochemical Journal ◽

10.1042/bj20101754 ◽

2011 ◽

Vol 436 (2) ◽

pp. 507-516 ◽

Cited By ~ 14

Author(s):

Heping Yang ◽

Tony W. H. Li ◽

Jian Peng ◽

José M. Mato ◽

Shelly C. Lu

Keyword(s):

Colon Cancer ◽

Growth Factor ◽

Protein Binding ◽

Cancer Cells ◽

Promoter Activity ◽

Human Colon ◽

Methionine Adenosyltransferase ◽

Insulin Like Growth Factor ◽

Colon Cancer Cells ◽

Human Colon Cancer

We have previously reported that the expression of MAT2A (methionine adenosyltransferase 2A) is increased in human colon cancer and in colon cancer cells treated with IGF-1 (insulin-like growth factor-1), which was required for its mitogenic effect. The aim of the present study was to elucidate the molecular mechanisms of IGF-1-mediated MAT2A induction. Nuclear run-on analysis confirmed that the increase in MAT2A expression lies at the transcriptional level. DNase I footprinting of the MAT2A promoter region revealed a similar protein-binding pattern in colon cancer and IGF-1-treated RKO cells. IGF-1 induced MAT2A promoter activity and increased nuclear protein binding to USF (upstream stimulatory factor)/c-Myb, YY1 (Yin and Yang 1), E2F, AP-1 (activator protein 1) and NF-κB (nuclear factor κB) consensus elements. IGF-1 increased the expression of c-Jun, FosB, MafG, p65, c-Myb, E2F-1 and YY1 at the pre-translational level. Knockdown of p65, MafG, c-Myb or E2F-1 lowered basal MAT2A expression and blunted the inductive effect of IGF-1 on MAT2A, whereas knockdown of YY1 increased basal MAT2A expression and had no effect on IGF-1-mediated MAT2A induction. Consistently, mutation of AP-1, NF-κB, E2F and USF/c-Myb elements individually blunted the IGF-1-mediated increase in MAT2A promoter activity, and combined mutations completely prevented the increase. In conclusion, IGF-1 activates MAT2A transcription by both known and novel pathways. YY1 represses MAT2A expression.

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