Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon

Lee, Seungkoo; Bang, Si Ra; Song, Kyuyoung; Lee, Inchul

doi:10.3892/or.16.4.747

Cited by 73 publications

(78 citation statements)

References 33 publications

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“…The ectopic expression of MTUS1 gene products has been shown to inhibit the cell proliferation [14,26]. The reduced expression of MTUS1 has been observed in colon cancer, ovarian cancer and pancreatic cancer [14,16,17]. These results, together with our study suggested that MTUS1 is a potential tumor suppressor gene for HNSCC and is a promising candidate for further functional analysis.…”

Section: Resultssupporting

confidence: 74%

Genomic assessments of the frequent loss of heterozygosity region on 8p21.3∼p22 in head and neck squamous cell carcinoma

Pungpravat

Huang

et al. 2007

Cancer Genetics and Cytogenetics

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Most human cancers are characterized by genetic instabilities. Chromosomal aberrations include segments of allelic imbalance identifiable by loss of heterozygosity (LOH) at polymorphic loci, which may be used to implicate regions harboring tumor suppressor genes. Here we performed whole genome LOH profiling on over 40 human head and neck squamous cell carcinoma (HNSCC) cell lines. Several frequent LOH regions have been identified on chromosomal arms 3p, 4p, 4q, 5q, 8p, 9p, 10p, 11q, and 17p. A genomic region of ∼7 Mb located at 8p22-p21.3 exhibits the most frequent LOH (87.9%), which suggested that this region harbors important tumor suppressor gene(s). Mitochondrial tumor suppressor gene 1 (MTUS1) is a recently identified candidate tumor suppressor gene that resides in this region. Consistent down-regulation in expression was observed in HNSCC for MTUS1 as measured by real-time quantitative RT-PCR. Sequence analysis of MTUS1 gene in HNSCC revealed several important sequence variants in the exon regions of this gene. Thus, our results suggested that MTUS1 is one of the candidate tumor suppressor gene(s) reside in 8p22-p21.3 for HNSCC. The identification of these candidate genes will facilitate the understanding of tumorigenesis of HNSCC. Further studies are needed to functionally evaluate those candidate genes.

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Section: Resultssupporting

confidence: 74%

Genomic assessments of the frequent loss of heterozygosity region on 8p21.3∼p22 in head and neck squamous cell carcinoma

Pungpravat

Huang

et al. 2007

Cancer Genetics and Cytogenetics

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“…Reduced PDCD4 expression has been reported in at least six human tumor types or cancer cell lines (lung, brain, renal, breast, colon and pancreas) (Chen et al, 2003;Jansen et al, 2004;Ma et al, 2005;Lee et al, 2006), out of the nine solid tumors in which miR-21 is overexpressed (Chan et al, 2005;Iorio et al, 2005;Diederichs and Haber, 2006;Roldo et al, 2006;Volinia et al, 2006), indicating that mir-21/PDCD4 is likely to be a clinically significant oncogene:tumor suppressor pair in the induction and progression of human carcinomas.…”

Section: Mir-21 Targets Pdcd4 Z Lu Et Almentioning

confidence: 99%

MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene

et al. 2008

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MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively control expression of target genes in animals and plants. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. We initiated a screen to identify miR-21 target genes using a reporter assay and identified a potential miR-21 target in the 3 0 -UTR of the programmed cell death 4 (PDCD4) gene. We cloned the full-length 3 0 -UTR of human PDCD4 downstream of a reporter and found that mir-21 downregulated, whereas a modified antisense RNA to miR-21 upregulated reporter activity. Moreover, deletion of the putative miR-21-binding site (miRNA regulatory element, MRE) from the 3 0 -UTR of PDCD4, or mutations in the MRE abolished the ability of miR-21 to inhibit reporter activity, indicating that this MRE is a critical regulatory region. Western blotting showed that Pdcd4 protein levels were reduced by miR-21 in human and mouse cells, whereas quantitative real-time PCR revealed little difference at the mRNA level, suggesting translational regulation. Finally, overexpression of mir-21 in MCF-7 human breast cancer cells and mouse epidermal JB6 cells promoted soft agar colony formation by downregulating Pdcd4 protein levels. The demonstration that miR-21 promotes cell transformation supports the concept that mir-21 functions as an oncogene by a mechanism that involves translational repression of the tumor suppressor Pdcd4.

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“…Previously, the inhibitory effect of MTUS1 on cell proliferation was linked to the growth inhibitory signaling cascade by trans-inactivation of receptor tyrosine kinases in insulin, bFGF, PDGF and EGF-induced ERK2 activation (17). A previously published investigation demonstrated a significant down-regulation of MTUS1 in ovarian carcinoma tissues, implicating a possible role of MTUS1 on the development of ovarian carcinoma (18 (19)(20)(21). The gene responsible for tumor progression in colon cancer, located at chromosome 8p21.3-22 near marker D8S254, would be expected to be down-regulated in colon cancer (1,10).…”

Section: Introdutionmentioning

confidence: 99%

Down-regulation of MTUS1 in human colon tumors

Zuern

Heimrich²,

Kaufmann³

et al. 2009

Oncol Rep

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Abstract. Loss of proliferative control and failure to undergo cellular differentiation are key events during carcinogenesis. We recently identified a new potential tumor suppressor gene named MTUS1 (mitochondrial tumor suppressor 1), downregulated in undifferentiated tumor cell lines, inhibiting tumor cell proliferation after recombinant over-expression. The aim of this study was to investigate whether MTUS1 is also down-regulated in human tumor tissues, and whether reduced expression of MTUS1 enhances cellular proliferation. Expression of MTUS1 in human colon cancer tissues was compared with corresponding normal colon tissues using Western blot analysis and RT-PCR. Investigation of the DNA sequence and methylation pattern was performed using bisulfite reaction and DNA sequencing. Promotor activity was measured by promoter assays. Silencing of MTUS1 was carried out by siRNA transfection. Proliferation was measured by cell count. MTUS1 expression is significantly down-regulated in colon cancer tissues, compared to the corresponding normal tissues, on protein and mRNA level. No mutations of MTUS1 were detected in the coding sequence or the predicted promoter region in cancer tissues. No difference of CpG methylation, but an altered CpNpG methylation was found in the predicted promoter region. Functional significance of the predicted promoter region was demonstrated by promoter assays. Down-regulation of the MTUS1 expression by siRNA transfection significantly increased cellular proliferation. This study demonstrates a significant down-regulation of the MTUS1 expression in human colon cancer tissues. Since reduced expression of MTUS1 results in increased cellular proliferation, these data suggest that MTUS1 could be involved in the loss of proliferative control in human colon cancer. IntrodutionThe multistage process of carcinogenesis includes the progressive acquisition of genetic alterations, resulting in activation of proto-oncogenes and inactivation of tumor suppressor genes. Consequential critical events in the evolution of tumors include the loss of proliferative control and the failure to undergo cellular differentiation. Genes located at chromosome 8p21.3-22 near marker D8S254 participate in tumor progression in colorectal cancer, pancreatic cancer, breast cancer, esophageal cancer, hepatocellular carcinoma, lung cancer, prostate cancer, urinary bladder carcinoma and head and neck squamous cell carcinoma (1-15). We previously identified a new gene named MTSG1, only <0.9 Mb apart from the D8S254 marker locus, regulating tumor cell proliferation (16). In accordance with the Guidelines for Human Gene Nomenclature it was recommended to change the gene name to MTUS1 (mitochondrial tumor suppressor 1), as it meanwhile appears in most databases. MTUS1 was discovered by investigating the molecular regulation during cellular transition from proliferation to senescence and differentiation in a three-dimensional collagen type I cell culture model. We thereby observed a transient up-regulation of MTUS1 during the init...

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Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon

Cited by 73 publications

References 33 publications

Genomic assessments of the frequent loss of heterozygosity region on 8p21.3∼p22 in head and neck squamous cell carcinoma

Genomic assessments of the frequent loss of heterozygosity region on 8p21.3∼p22 in head and neck squamous cell carcinoma

MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene

Down-regulation of MTUS1 in human colon tumors

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