Identification of Novel Candidate Oncogenes and Tumor Suppressors in Malignant Pleural Mesothelioma Using Large-Scale Transcriptional Profiling

Gordon, Gavin J.; Rockwell, Graham N.; Jensen, Roderick V.; Rheinwald, James G.; Glickman, Jonathan N.; Aronson, Joshua P.; Pottorf, Brian J.; Nitz, Matthew D.; Richards, William G.; Sugarbaker, David J.; Bueno, Raphael

doi:10.1016/s0002-9440(10)62492-3

Cited by 170 publications

(185 citation statements)

References 57 publications

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“…47,48 Based on the analysis of mRNA microarray expression data obtained from the Oncomine database, CHCHD2 is overexpressed in a diverse group of cancers, including prostate, lung, kidney, skin, brain, mesothelium, head and neck and two types of leukemias (Table 1). [49][50][51][52][53][54][55][56][57][58][59][60][61] The upregulation of CHCHD2 in cancers along with our data showing that CHCHD2 knockdown sensitizes cancer cells to chemotherapeutic agents suggests that further research investigating CHCHD2 as a cancer biomarker or as a potential chemosensitizing drug target may be warranted.…”

Section: Chchd2 Inhibits Apoptosis Y Liu Et Almentioning

confidence: 57%

CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation

et al. 2014

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Mitochondrial outer membrane permeabilization (MOMP) is a critical control point during apoptosis that results in the release of pro-apoptotic mitochondrial contents such as cytochrome c. MOMP is largely controlled by Bcl-2 family proteins such as Bax, which under various apoptotic stresses becomes activated and oligomerizes on the outer mitochondrial membrane. Bax oligomerization helps promote the diffusion of the mitochondrial contents into the cytoplasm activating the caspase cascade. In turn, Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL, which was recently shown to prevent Bax from accumulating at the mitochondria. However, the exact mechanisms by which Bcl-xL regulates Bax and thereby MOMP remain partially understood. In this study, we show that the small CHCH-domain-containing protein CHCHD2 binds to Bcl-xL and inhibits the mitochondrial accumulation and oligomerization of Bax. Our data show that in response to apoptotic stimuli, mitochondrial CHCHD2 decreases prior to MOMP. Furthermore, when CHCHD2 is absent from the mitochondria, the ability of Bcl-xL to inhibit Bax activation and to prevent apoptosis is attenuated, which results in increases in Bax oligomerization, MOMP and apoptosis. Collectively, our findings establish CHCHD2, a previously uncharacterized small mitochondrial protein with no known homology to the Bcl-2 family, as one of the negative regulators of mitochondria-mediated apoptosis.

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Section: Chchd2 Inhibits Apoptosis Y Liu Et Almentioning

confidence: 57%

CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation

et al. 2014

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“…To assess whether read counts (i.e., the number of reads that mapped to a given mRNA) can quantify relative transcript levels, we focused on six specific transcripts known to be differentially expressed in MPM and ADCA, which in combination can be used as a genomic test to distinguish the two tumor types (22,23). The calculated geometric combination of the three expression ratios of these six genes obtained through real-time PCR or microarrays can be used to distinguish MPM from ADCA.…”

Section: Resultsmentioning

confidence: 99%

“…The horizontal asymptote represents Ϸ17,000 of the Known RefSeq Genes detected by at least one read in any of the four MPM samples, which encompassed a total of 7 million reads. (B) Classification of tumor specimens using read counts to calculate gene expression ratios for six known diagnostic genes and their geometric mean (23). Ratios correctly identified each tumor type (i.e., Ͼ1, MPM; Ͻ1, ADCA).…”

Section: Rules For Single Nucleotide Substitution Variant (Snv) ‡ ‡ Dmentioning

confidence: 99%

Transcriptome sequencing of malignant pleural mesothelioma tumors

Sugarbaker

Richards²,

Gordon³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Cancers arise by the gradual accumulation of mutations in multiple genes. We now use shotgun pyrosequencing to characterize RNA mutations and expression levels unique to malignant pleural mesotheliomas (MPMs) and not present in control tissues. On average, 266 Mb of cDNA were sequenced from each of four MPMs, from a control pulmonary adenocarcinoma (ADCA), and from normal lung tissue. Previously observed differences in MPM RNA expression levels were confirmed. Point mutations were identified by using criteria that require the presence of the mutation in at least four reads and in both cDNA strands and the absence of the mutation from sequence databases, normal adjacent tissues, and other controls. In the four MPMs, 15 nonsynonymous mutations were discovered: 7 were point mutations, 3 were deletions, 4 were exclusively expressed as a consequence of imputed epigenetic silencing, and 1 was putatively expressed as a consequence of RNA editing. Notably, each MPM had a different mutation profile, and no mutated gene was previously implicated in MPM. Of the seven point mutations, three were observed in at least one tumor from 49 other MPM patients. The mutations were in genes that could be causally related to cancer and included XRCC6, PDZK1IP1, ACTR1A, and AVEN.DNA sequencing ͉ tumor mutations ͉ lung cancer ͉ bioinformatics ͉ loss of heterozygosity B ecause cancer arises as a consequence of multiple mutations, human cancer genomes are being sequenced to identify the mechanisms of tumorigenesis. Pilot sequencing studies include recent exon resequencing of tumors and cell lines that revealed somatic mutations in hundreds of genes not previously implicated in oncogenesis. These studies generally focused on a single class of mutations such as point mutations in coding regions of preselected candidate genes, and the results so far indicate that even within similar histological classes, tumors possess unique mutational profiles (1-3). However, there has rarely been an analysis of whether a mutated gene is actually expressed in the tumor cell nor has there been an attempt to use sequencing to identify other types of mutations such as chromosomal deletions or translocation (4, 5) or loss of heterozygosity related to epigenetic silencing (6, 7). Moreover, no unbiased deep sequencing analysis of all expressed genes in cancer tissues has been reported to date.Malignant pleural mesothelioma (MPM) is an asbestosrelated, rapidly fatal cancer. Its genetic basis is unknown but appears to involve multiple types of chromosomal abnormalities (5,(8)(9)(10)(11)(12)(13)(14). Central mechanisms underlying MPM are unclear, although MPM tumors evoke a strong inflammatory response thought to contribute to tumorigenesis (15). In addition, tumor cell survival promoted by TNF-␣ responsive antiapoptotic proteins such as Inhibitor of Apoptosis-1 (IAP-1) facilitates the resistance of MPM to most cytotoxic chemotherapeutic drugs (16). Expression profiling with microarrays has supported the general role of inflammation in MPM etiology and has provided...

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“…Pass et al (2004) and Gordon et al (2003) have identified distinct signatures of prognosis in resected pleural mesothelioma, which interestingly were independent of histology subtype. More recently, Gordon et al (2005) used unsupervised clustering to identify three groups of tumors, two of which were comprised primarily of epithelial and biphasic tumors, respectively. Together, these results suggest that molecular signatures distinguish these subtypes in both peritoneal and pleural malignant mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

et al. 2006

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Identification of Novel Candidate Oncogenes and Tumor Suppressors in Malignant Pleural Mesothelioma Using Large-Scale Transcriptional Profiling

Cited by 170 publications

References 57 publications

CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation

CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation

Transcriptome sequencing of malignant pleural mesothelioma tumors

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

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