Identification of the Retinoic Acid-Inducible Gprc5a As a New Lung Tumor Suppressor Gene

Tao, Qingguo; Fujimoto, Junya; Men, Taoyan; Ye, Xiaofeng; Deng, Jiong; Lacroix, Ludovic; Clifford, John L.; Li, Mao; Pelt, Carolyn S. Van; Lee, John; Lotan, Dafna; Lotan, Reuben

doi:10.1093/jnci/djm208

Cited by 106 publications

(205 citation statements)

References 46 publications

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“…GPRC5A was recently reported as a lung tumor suppressor (Tao et al, 2007). In the present analysis, we did not focus on this gene, as its expression was not clearly upregulated in SNB78 cells that were treated with ACSL5 siRNAs (data not shown).…”

Section: Other Factors Affected By Acsl5mentioning

confidence: 83%

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Mashima

Sato²,

Sugimoto

et al. 2008

Oncogene

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Extracellular acidosis (low pH) is a tumor microenvironmental stressor that has a critical function in the malignant progression and metastatic dissemination of tumors. To survive under stress conditions, tumor cells must evolve resistance to stress-induced toxicity. AcylCoA synthetase 5 (ACSL5) is a member of the ACS family, which converts fatty acid to acyl-CoA. ACSL5 is frequently overexpressed in malignant glioma, whereas its functional significance is still unknown. Using retrovirusmediated stable gene transfer (gain of function) and small interfering RNA-mediated gene silencing (loss of function), we show here that ACSL5 selectively promotes human glioma cell survival under extracellular acidosis. ACSL5 enhanced cell survival through its ACS catalytic activity. To clarify the genome-wide changes in cell signaling pathways by ACSL5, we performed cDNA microarray analysis and identified an ACSL5-dependent gene expression signature. The analysis revealed that ACSL5 was critical to the expression of tumor-related factors including midkine (MDK), a heparin-binding growth factor frequently overexpressed in cancer. Knockdown of MDK expression significantly attenuated ACSL5-mediated survival under acidic state. These results indicate that ACSL5 is a critical factor for survival of glioma cells under acidic tumor microenvironment, thus providing novel molecular basis for cancer therapy.

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Section: Other Factors Affected By Acsl5mentioning

confidence: 83%

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Mashima

Sato²,

Sugimoto

et al. 2008

Oncogene

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“…this locus is within suspected tumor-suppressor gene GPRC5A (Tao et al 2007;Acquafreda et al 2009), suggesting the possibility that persistent STAT3 activation due to mutation of GPRC5A ) may be a contributing factor in these patients. Interestingly, both samples 10-822 [carrying the t(17;19)] and 10-838 were from relapsed patients who eventually died of their disease, suggesting that GPRC5A disruption should be investigated for potential prognostic significance.…”

Section: Deregulation Of Replication Domains In Leukemiamentioning

confidence: 99%

Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia

et al. 2012

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Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replicationtiming profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replicationtiming domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.

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“…GPRC5A is predominately expressed in lung tissue (6)(7)(8)(9), suggesting that it may be important for homeostasis of lung tissue. GPRC5A gene locus is at 12p13.…”

Section: Introductionmentioning

confidence: 99%

“…LOH (loss of heterozygosity) of chromosome 12p was found to frequently occur in NSCLCs (10,11). In addition, GPRC5A was significantly repressed in most of NSCLC (8,12) and all of chronic obstructive pulmonary disease tissues. Gprc5a gene knockout (ko; Gprc5a À/À ) mice appeared to have normal lung development (9).…”

Section: Introductionmentioning

confidence: 99%

Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling

et al. 2015

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Identification of the Retinoic Acid-Inducible Gprc5a As a New Lung Tumor Suppressor Gene

Abstract: Gprc5a functions as a tumor suppressor in mouse lung, and human GPRC5A may share this property. The Gprc5a-deficient mouse is a novel model to study lung carcinogenesis and chemoprevention.

Cited by 106 publications

References 46 publications

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia

Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling

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