A catalog of genes homozygously deleted in human lung cancer and the candidacy of <i>PTPRD</i> as a tumor suppressor gene

Kohno, Takashi; Otsuka, Ayaka; Girard, Luc; Sato, Masanori; Iwakawa, Reika; Ogiwara, Hideaki; Sanchez-Cespedes, Montse; Minna, John D.; Yokota, Jun

doi:10.1002/gcc.20746

Cited by 78 publications

(82 citation statements)

References 50 publications

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“…The low-density lipoprotein receptor-related protein gene (LRP1B) originally isolated on the basis of homozygous deletions detected in human lung cancer cell lines (Liu et al, 2000a(Liu et al, , 2000bKohno et al, 2010) was recently reported among the top 10 most significantly deleted genes across 3312 human cancer specimens (Beroukhim et al, 2010). LRP1B encodes for a member of the endocytic low-density lipoprotein receptor superfamily.…”

Section: Introductionmentioning

confidence: 99%

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

et al. 2010

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The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells.

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Section: Introductionmentioning

confidence: 99%

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

et al. 2010

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“…Homozygous deletion of PTPRD has been reported at a frequency of 8-20% in lung cancer, melanoma, neuroblastoma, glioblastoma multiforme, laryngeal SCC and lymphoma. [13][14][15][16][17][18][19] Mutations of the coding exons of PTPRD and methylation at the promoter region have also been reported in lung cancer, melanoma, glioblastoma, breast and colorectal cancers, indicating that multiple mechanisms of disruption affect this gene in cancer. 17,[20][21][22] The overexpression of PTPRD in vitro causes transient growth arrest and an increase in apoptotic cells, with the converse demonstrated for the knockdown of PTPRD.…”

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confidence: 99%

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Lambert

Harwood

Purdie

et al. 2011

Intl Journal of Cancer

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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p 5 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.Nonmelanoma skin cancer (NMSC) has a predicted prevalence equal to that of all other cancers combined and its incidence is increasing.1 There are more than 81,500 new cases of NMSC diagnosed annually in the United Kingdom alone, placing a heavy burden on both patients and healthcare resources.2 Despite accounting for only 20% of total NMSC cases, cutaneous squamous cell carcinoma (cSCC) is responsible for the majority of NMSC deaths, largely as a result of metastatic disease. A subset of immunosuppressed individuals, such as organ transplant recipients on long-term immunosuppressive drugs, develop particularly aggressive tumors with an increased risk of metastasis.3 Risk factors for metastasis include poor differentiation of the tumor cells, large tumor size, tumor depth >5 mm, immunosuppression and localization on the ear and lip. [4][5][6][7] Metastatic cSCC is currently treated by surgical intervention and/or chemotherapy or radiotherapy and is associated with a poor outcome. 8Despite the well-established role of ultraviolet radiation (UVR) in the etiology of cSCC, the molecular events underlying its development remain largely undefined. Inactivation of the tumor suppressor genes TP53 and p16INK4A is a common and early event in cSCC pathogenesis and is characteristic of all histological grades of tumor. 9,10 Recently, genotyping of 60 cSCC identified high rates of loss of heterozygosity (LOH)

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“…This result might indicate that the ability of Nrf2 protein to degrade under homeostatic conditions varies among different cell lines. Several reports indicated a relationship between Keap1 mutation and poor prognosis or chemoresistance in NSCLC cell lines and tumors (31)(32)(33). Keap1 mutations are present in a series of NSCLC cell lines that were used in this study (Supplementary Table S1).…”

Section: Discussionmentioning

confidence: 91%

Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501In Vitro

Mine¹,

Yamamoto²,

Küfe

et al. 2014

Molecular Cancer Therapeutics

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CBP501 is an anticancer drug candidate that was investigated in two randomized phase II clinical trials for patients with nonsquamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). CBP501 has been shown to have two mechanisms of action, namely calmodulin modulation and G 2 checkpoint abrogation. Here, we searched for a biomarker to predict sensitivity to CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501-sensitive and -insensitive, by quantitatively analyzing the cisdiamminedichloro-platinum (II) (CDDP)-enhancing activity of CBP501 through treatments with short-term (1 hour) coexposure to CDDP and CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with CBP501 sensitivity. We found that multiple nuclear factor erythroid-2-related factor 2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines. Western blot and immunocytochemical analysis for Nrf2 in NSCLC cell lines also indicated higher protein level in CBP501-insensitive cell lines. Moreover, CBP501 sensitivity is modulated by silencing or sulforaphane-induced overexpression of Nrf2. These results indicate that Nrf2 transcription factor is a potential candidate as a biomarker for resistance to CBP501. This study might help to identify those subpopulations of patients who would respond well to the CBP501 and CDDP combination treatment of NSCLC. Mol Cancer Ther; 13(9); 2215-25. Ó2014 AACR.

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A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene

Cited by 78 publications

References 50 publications

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501In Vitro

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