Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses

Kleivi, Kristine; Lind, Guro Elisabeth; Diep, Chieu B.; Meling, Gunn Iren; Brandal, Lin Thorstensen; Nesland, Jahn M.; Myklebost, Ola; Rognum, Torleiv O.; Giercksky, Karl Erik; Skotheim, Rolf Inge; Lothe, Ragnhild

doi:10.1186/1476-4598-6-2

Cited by 63 publications

(44 citation statements)

References 67 publications

(63 reference statements)

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“…20, 21, 34, 52 Earlier, it was shown that SUB1 is amplified and over-expressed in the NSCLC cell lines, 53 invasive intraductal papillary mucinous neoplasm of the pancreas 54 and in carcinomatoses. 55 Additionally, it has been shown that exogenous overexpression of SUB1 could induce the transformation of a population of normal dermal multipotent fibroblasts to acquire malignant characteristics of anchorage-independent growth in vitro and tumorigenicity in nude mice. 56 Additionally, it was reported that SUB1 is upregulated in esophageal squamous cell carcinoma (ESCC) and its absence increased radiosensitivity of ESCC cells, and suppressed non-homologous end joining (NHEJ) activity via downregulation of XLF.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

et al. 2016

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MicroRNA-101, a tumor suppressor microRNA is often down-regulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2, COX2, POMP, CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that mir-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to play diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as polo-like kinase PLK1, C-MYC, serine threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 down-regulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in the prostate cancer and identifies its regulation, and potential downstream therapeutic targets of SUB1 in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

et al. 2016

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“…Two studies used home-made cDNA microarrays [8], [13], one used the Agilent human 1A platform [9], and the last one used home-spotted chips using the Sigma human Oligolibrary [11]. Because these platforms did not use Affymetrix probes, we first converted our probe signature into a gene signature.…”

Section: Resultsmentioning

confidence: 99%

“…Two studies presented gene signatures associated with metastatic disease containing more than 400 genes. Such long lists of genes are difficult to use for the development of new therapies [9], [10]. Among the five studies aimed at identifying the molecular mechanisms taking place during metastatic dissemination and growth, two did not succeed in the identification of a signature able to clearly separate primary cancers from metastatic tissues.…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that heterogeneity between patients is higher than between a primary tumor and its metastases. Finally, the three gene signatures published so far [9], [13], [14] share only few genes [8], underlining the difficulty of extracting pertinent data from the background due to human diversity, cancer heterogeneity and the use of different microarray platforms.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the difficulty of getting a robust signature from clinical samples, several authors have used model cell lines to identify genes associated with metastatic dissemination [9],[15],[16]. However, if working with cell lines will solve the problem of inter-individual variations, tissues and corresponding cell lines have different gene expression profiles [17].…”

Section: Introductionmentioning

confidence: 99%

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Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

et al. 2013

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To identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment.

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Gene expression in colon cancer: A focus on tumor site and molecular phenotype

Slattery

Pellatt

Mullany

et al. 2015

Genes Chromosomes & Cancer

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Hundreds to thousands of genes are differentially expressed in tumors when compared to nontumor colonic tissue samples. We evaluated gene expression patterns to better understand differences in colon cancer by tumor site and tumor molecular phenotype. We analyzed RNA-seq data from tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy with nonparametric tests to identify genes which displayed varying expression characteristics related to paired tumor/nontumor tissue across proximal and distal colon sites and by tumor molecular phenotypes, that is, TP53, KRAS, CpG Island Methylator Phenotype (CIMP), and microsatellite instability (MSI). We used Ingenuity Pathway Analysis (IPA) to determine networks associated with deregulated genes in our data. Genes showed significant differences in expression characteristics at the 0.01 level in both validation groups between tumor subsite (116 genes), CIMP high versus CIMP low (79 genes), MSI versus microsatellite stable (MSS) (49 genes), TP53-mutated versus not mutated (17genes), and KRAS-mutated versus not mutated (1 gene). Deregulated genes for CIMP high and MSI tumors were often down-regulated. In contrast to CIMP high and MSI tumors, genes that were deregulated in TP53 were likely to be up-regulated. ERK1, WNT, growth factors and inflammation-related factors were focal points of both CIMP and MSI IPA networks. The MUC family of genes was up-regulated MSI networks. Numerous genes showed differences in expression between proximal and distal tumors, nontumor proximal and distal tissue, and tumor molecular phenotype. Deregulated mucin genes appear to play an important role in MSI tumors.

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Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses

Cited by 63 publications

References 67 publications

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

Gene expression in colon cancer: A focus on tumor site and molecular phenotype

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