Computational analysis for identification of the extracellular matrix molecules involved in endometrial cancer progression

Abstract

Recurrence and poorly differentiated (grade 3 and above) and atypical cell type endometrial cancer (EC) have poor prognosis outcome. The mechanisms and characteristics of recurrence and distal metastasis of EC remain unclear. The extracellular matrix (ECM) of the reproductive tract in women undergoes extensive structural remodelling changes every month. Altered ECMs surrounding cells were believed to play crucial roles in a cancer progression. To decipher the associations between ECM and EC development, we generated a PAN-ECM Data list of 1516 genes including ECM molecules (ECMs), synthetic and degradation enzymes for ECMs, ECM receptors, and soluble molecules that regulate ECM and used RNA-Seq data from The Cancer Genome Atlas (TCGA) for the studies. The alterations of PAN-ECM genes by comparing the RNA-Seq expressions profiles of EC samples which have been grouped as tumorigenesis and metastasis group based on their pathological grading were identified. Differential analyses including functional enrichment, co-expression network, and molecular network analysis were carried out to identify the specific PAN-ECM genes that may involve in the progression of EC. Eight hundred and thirty-one and 241 PAN-ECM genes were significantly involved in tumorigenesis (p-value <1.571e-15) and metastasis (p-value <2.2e-16), respectively, whereas 140 genes were in the intersection of tumorigenesis and metastasis. Interestingly, 92 of the 140 intersecting PAN-ECM genes showed contrasting fold changes between the tumorigenesis and metastasis datasets. Enrichment analysis for the contrast PAN-ECM genes indicated pathways such as GP6 signaling, ILK signaling, and interleukin (IL)-8 signaling pathways were activated in metastasis but inhibited in tumorigenesis. The significantly activated ECM and ECM associated genes in GP6 signaling, ILK signaling, and interleukin (IL)-8 signaling pathways may play crucial

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

“…The enrichment of this pathway in PCs suggests that parathyroid cancer development might follow shared patterns with the mechanisms of liver fibrosis. At variance with endometrial cancer in which GP6 signaling pathway was inhibited in early stage but activated in late stage of tumorigenesis we found that this pathway was activated both in the non-metastatic and metastatic PCs (Yadav et al 2020). Of note, the Z-score and the significance of the comparisons between both metastatic PCs and non-metastatic PCs vs PAs was much higher than in the comparison between metastatic and non-metastatic PCs, suggesting that it might have a role in the early phase of parathyroid tumorigenesis.…”

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma

“…Interestingly, part of these differentially methylated genes was involved in biological processes related to cell adhesion and ECM organization. Of note, both biological pathways play a major role in invasion and migration of several types of tumors, including uterine neoplasms ( Abal et al, 2007 ; Yadav et al, 2020 ), suggesting that epigenetic disruption of these pathways could influence the metastatic properties of uADC and uLMS. In addition, combining transcriptomic and epigenomic analysis, we observed an association between the methylation status of CGI promoters and expression in a set of 20 genes, implying epigenetic regulation of these genes in ITF.…”

Expression of extracellular matrix proteins nidogen‐1 and legumain in endometrial carcinomas

“…The extracellular matrix (ECM) of the female reproductive tract experiences broad changes including structural remodeling each month. Changed ECM components around cells are considered to play significant roles in the development of cancer 2 …”

“…Changed ECM components around cells are considered to play significant roles in the development of cancer. 2 Legumain (LGMN) is a cysteine endopeptidase that specifically hydrolyzes substrate asparaginyl bonds.…”