Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Espinal-Enríquez, Jesús; Muñoz-Montero, Said; Imaz-Rosshandler, Iván; Huerta-Verde, Aldo J; Mejía, Carmen; Hernández‐Lemus, Enrique

doi:10.1186/s12864-015-1372-0

Cited by 32 publications

(26 citation statements)

References 55 publications

(65 reference statements)

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“…CDH1, an important regulator of epithelial-mesenchymal transition, has likewise been shown to be downregulated in ATC (32,33). Conversely, matrix metalloproteinase-1 (MMP1), important for allowing invasion and metastasis, is highly overexpressed in ATC (16,34). Poorly differentiated thyroid carcinoma specimens have profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (35).…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Weinberger

Ponny

et al. 2017

Thyroid

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Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that ''mitotic cell cycle'' is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10 -30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 99%

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Weinberger

Ponny

et al. 2017

Thyroid

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“…RAB12 is a Ras oncogene family member and is overexpressed in colorectal cancers (44). Furthermore, the COLEC12 gene is known prognostic marker in anaplastic thyroid cancer and brain tumors (45,46). Because of limited clinical annotation of the TCGA data, we were unable to validate these as prognostic markers in the TCGA cohort.…”

Section: Discussionmentioning

confidence: 99%

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

et al. 2016

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Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n ¼ 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11. 21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged.

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“…Met. Anaplastic thyroid carcinoma ↓ (RNA) [ 90 ] / GSTM2 −3.10 < 0.001 Drug Met. Barett’s esophagus ↓ (RNA) [ 27 ] Associated to DNA hypermethylation [ 27 , 91 ].…”

Section: Resultsmentioning

confidence: 99%

A transcriptome-based protein network that identifies new therapeutic targets in colorectal cancer

et al. 2017

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BackgroundColon cancer occurrence is increasing worldwide, making it the third most frequent cancer. Although many therapeutic options are available and quite efficient at the early stages, survival is strongly decreased when the disease has spread to other organs. The identification of molecular markers of colon cancer is likely to help understanding its course and, eventually, to uncover novel genes to be targeted by drugs. In this study, we compared gene expression in a set of 95 human colon cancer samples to that in 19 normal colon mucosae, focusing on 401 genes from 5 selected pathways (Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism, Wnt/beta-catenin). Deregulation of mRNA levels largely matched that of proteins, leading us to build in silico protein networks, starting from mRNA levels, to identify key proteins central to network activity.ResultsAmong the analyzed genes, 10.5% (42) had no reported link with colon cancer, including the SFRP1, IGF1 and ADH1B (down), and MYC and IL8 (up), whose encoded proteins were most interacting with other proteins from the same or even distinct networks. Analyzing all pathways globally led us to uncover novel functional links between a priori unrelated or rather remotely connected pathways, such as the Drug metabolism and the Cancer pathways or, even more strikingly, between the Cholesterol metabolism and lipoprotein signaling and the Cancer pathways. In addition, we analyzed the responsiveness of some of the deregulated genes essential to network activities, to chemotherapeutic agents used alone or in presence of Lovastatin, a lipid-lowering drug. Some of these treatments could oppose the deregulations occurring in cancer samples, including those of the CHECK2, CYP51A1, HMGCS1, ITGA2, NME1 or VEGFA genes.ConclusionsOur network-based approach allowed discovering genes not previously known to play regulatory roles in colon cancer. Our results also showed that selected drug treatments might revert the cancer-specific deregulation of genes playing prominent roles within the networks operating to maintain colon homeostasis. Among those genes, some could constitute novel testable targets to eliminate colon cancer cells, either directly or, potentially, through the use of lipid-lowering drugs such as statins, in association with selected anticancer drugs.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4139-y) contains supplementary material, which is available to authorized users.

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Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Cited by 32 publications

References 55 publications

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

A transcriptome-based protein network that identifies new therapeutic targets in colorectal cancer

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