Experimental trial for diagnosis of pancreatic ductal carcinoma based on gene expression profiles of pancreatic ductal cells

Ishikawa, Madoka; Yoshida, Kōji; Yamashita, Yuichi; Ota, Jun; Takada, Shuji; Kisanuki, Hiroyuki; Koinuma, Koji; Choi, Young Lim; Kaneda, Ruri; Iwao, Toshiyasu; Tamada, Kiichi; Sugano, Kentaro; Mano, Hiroyuki

doi:10.1111/j.1349-7006.2005.00064.x

Cited by 82 publications

(57 citation statements)

References 21 publications

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“…Moreover, when we split the series to assess survival of patients with above or below median CHCHD4 expression, we found that CHCHD4 expression above the median was associated with a significantly poorer survival outcome (P = 0.016, log-rank test; Figure 6C). Confirming these findings, analysis of the microarray data from 3 independently published studies (35)(36)(37) showed that CHCHD4 expression was higher in pancreatic cancer compared with that in normal pancreatic tissue ( Figure 6D), and in breast cancer, increasing CHCHD4 expression correlated with increasing tumor grade ( Figure 6E). Furthermore, analyses of CHCHD4 expression in glioma (37) showed that increasing CHCHD4 expression correlated with increasing tumor grade ( Figure 6F) and reduced survival ( Figure 6G).…”

Section: Chchd4 Encodes 2 Alternatively Spliced and Differentially Exmentioning

confidence: 57%

“…Overexpression of HIF-α occurs in many human cancers and correlates with increased hypoxia, angiogenesis and metastasis, treat- ) analyzed from gene expression profiling data described previously (35). P = 0.005.…”

Section: Discussionmentioning

confidence: 99%

“…The study from Ishikawa et al includes 25 normal pancreatic duct cells and 24 pancreatic ductal carcinoma samples (GEO accession no. GSE1542) (35). Gene expression profiling was performed using the Affymetrix Human Genome U133A and U133B.…”

Section: Methodsmentioning

confidence: 99%

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Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

Yang¹,

Staples²,

Thomas³

et al. 2012

J. Clin. Invest.

142

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Increased expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins contain an evolutionarily conserved coiled-coil-helix-coiled-coilhelix (CHCH) domain important for mitochondrial localization. Modulation of CHCHD4 protein expression in tumor cells regulated cellular oxygen consumption rate and metabolism. Targeting CHCHD4 expression blocked HIF-1α induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells enhanced HIF-1α protein stabilization in hypoxic conditions, an effect insensitive to antioxidant treatment. In human cancers, increased CHCHD4 expression was found to correlate with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. Thus, our study identifies a mitochondrial mechanism that is critical for regulating the hypoxic response in tumors.

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Section: Chchd4 Encodes 2 Alternatively Spliced and Differentially Exmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

Yang¹,

Staples²,

Thomas³

et al. 2012

J. Clin. Invest.

142

View full text Add to dashboard Cite

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“…7 Third, published microarray studies reveal frequent alteration (both up-and downregulation) of RABL6A mRNA levels in PDAC tumors. [13][14][15][16] In this study, we evaluated RABL6A expression levels in human PDAC cell lines and in resected PDAC tumors from patients and correlated the latter with clinicopathological variables and survival. We also assessed how its depletion affected pancreatic cancer cell growth, survival, and responsiveness to PDAC chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients

et al. 2013

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy.

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“…Furthermore, pancreatic adenocarcinoma tissues contain a significant amount of adjacent normal tissue. 32,33 Because of this, our candidate pancreas markers were enriched for genes elevated in pancreas adenocarcinoma relative to normal pancreas cells. As a result of this approach, we identified a novel pancreas cancer-specific marker, coagulation factor V (F5).…”

Section: Marker Candidate Selectionmentioning

confidence: 99%

A Quantitative Reverse Transcriptase-Polymerase Chain Reaction Assay to Identify Metastatic Carcinoma Tissue of Origin

Talantov

Baden

Jatkoe

et al. 2006

The Journal of Molecular Diagnostics

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Identifying the primary site in patients with metastatic carcinoma of unknown primary origin can enable more specific therapeutic regimens and may prolong survival. Twenty-three putative tissue-specific markers for lung, colon, pancreatic, breast, prostate, and ovarian carcinomas were nominated by querying a gene expression profile database and by performing a literature search. Ten of these marker candidates were then selected based on validation by reverse transcriptase-polymerase chain reaction (RT-PCR) on 205 formalin-fixed, paraffin-embedded metastatic carcinoma specimens originating from these six and from other cancer types. Next, we optimized the RNA isolation and quantitative RT-PCR methods for these 10 markers and applied the quantitative RT-PCR assay to a set of 260 metastatic tumors. We then built a gene-based algorithm that predicted the tissue of origin of metastatic carcinomas with an overall leaveone-out cross-validation accuracy of 78%. Lastly, our assay demonstrated an accuracy of 76% when tested on an independent set of 48 metastatic samples, 37 of which were either a known primary or initially presented as carcinoma of unknown primary but were subsequently resolved.

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Experimental trial for diagnosis of pancreatic ductal carcinoma based on gene expression profiles of pancreatic ductal cells

Cited by 82 publications

References 21 publications

Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients

A Quantitative Reverse Transcriptase-Polymerase Chain Reaction Assay to Identify Metastatic Carcinoma Tissue of Origin

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