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A novel variant of human Grb7 is associated with invasive esophageal carcinoma.

ABSTRACT: The cDNAs of a putative growth factor-bound (Grb) 7 signal transduction molecule and Grb7V novel splice variant were isolated from an invasive human esophageal carcinoma. Although both Grb7 isoforms share homology with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 base pairs in the C terminus; the resultant frame shift leads to substitution of an SH2 domain with a short hydrophobic sequence. The wild-type Grb7 protein, but not the Grb7V isoform, is rapidly tyrosyl phosphorylated in response to EGF stimulation in esophageal carcinoma cells. Analysis of human esophageal tumor tissues and regional lymph nodes with metastases revealed that Grb7V was expressed in 40% of Grb7-positive esophageal carcinomas. More importantly, Grb7V expression was enhanced after metastatic spread to lymph nodes as compared to the original tumor tissues. Finally, transfection of an antisense Grb7 RNA expression construct lowered endogenous Grb7 protein levels and suppressed the invasive phenotype exhibited by esophageal carcinoma cells. These findings suggest that Grb7 isoforms are involved in cell invasion and metastatic progression of human esophageal carcinomas.

SUBMITTER: Tanaka S

PROVIDER: S-EPMC508945 | biostudies-other | 1998 Aug

REPOSITORIES: biostudies-other

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A novel variant of human Grb7 is associated with invasive esophageal carcinoma.

Tanaka S S Mori M M Akiyoshi T T Tanaka Y Y Mafune K K Wands J R JR Sugimachi K K

The Journal of clinical investigation 19980801 4

The cDNAs of a putative growth factor-bound (Grb) 7 signal transduction molecule and Grb7V novel splice variant were isolated from an invasive human esophageal carcinoma. Although both Grb7 isoforms share homology with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 base pairs in the C terminus; the resultant frame shift leads to substitution of an SH2 domain with a short hydrophobic sequence. The wild-type Grb7 protein, but not the Grb7V isoform, is rapidly tyrosyl phosphorylated in ...[more]

PMID: 9710451

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Project description:Breast carcinoma (BC) is the leading cause of death in women worldwide, making up 23% of all cancers in women, with 1.38 million new cases worldwide annually and responsible for 460,000 deaths. Despite the significant advances in the identification of molecular markers and different modalities of treatment in primary BC, the ability to predict the metastatic behavior in breast cancer is still limited. The purpose of this study was to help identify novel molecular markers associated with clinical outcome in a cohort of Brazilian BC patients. We generated global gene expression profiles from 24 patients with invasive ductal BC followed for â¥ 5-years, including 15 samples from patients classified as presenting good prognosis based on traditional markers and clinical criteria and 9 patients that developed metastasis. We identified a set of 58 differentially expressed genes (p â¤0.01) between groups of patients with good and poor prognosis. Up-regulation of B3GNT7, PPM1D, TNKS2, PHB and GTSE1 in patients with poor prognosis was confirmed by quantitative RT-PCR in an independent sample set from patients with BC (47 with good prognosis and 8 that presented metastasis). Expression of BAD protein was investigated by immunohistochemistry in 1276 BC samples and confirmed the reduced expression levels in metastatic cases observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinoma samples according to clinical course and progression of the disease. Global expression profiles from 38 ductal breast tumor patient samples were used to search for molecular signatures correlated with current prognostic markers. A subset of 24 cases comprising 15 patients that remained free of disease after surgery and 9 patients that developed metastasis was used to identify candidate biomarkers associated with metastatic progression. Candidates were subsequently validated in additional independent samples by RT-qPCR or immunohistochemistry.

Project description:Background: The incidence of human papillomavirus (HPV) associated oropharyngeal carcinomas has increased rapidly over the last thirty years. These tumours behave as a distinct biological entity when compared to classical smoking- and alcohol-related disease. To gain more information regarding the pathway through pre-malignancy in HPV positive/HPV negative oropharyngeal carcinoma (OSCC), we investigated genomewide expression profiles in histopathologically confirmed tumour samples with site-matched normal epithelial controls. Methods: Twenty-four patients with primary oropharyngeal squamous cell carcinoma (4 with stage III and 20 with stage IV disease) were included in this prospective clinical trial (UKCRN11945). The tumour tissues were each assessed by a histopathologist with HPV status and typing by p16INK4A, consensus PGMY PCR, type-specific HPV16 DNA & RNA PCR and DNA sequencing. Fresh tissue samples were subjected to whole transcriptome analysis using the Illumina Bead Array (~47,000 transcripts) and the results validated with quantitative Real Time-PCR (qRT-PCR). In a separate cohort of twelve OSCC patients, laser capture micro-dissection of formalin fixed paraffin embedded (FFPE) tissue allowed RNA extraction from regions of in situ malignant change (with matched normal and invasive SCC samples). Results: The majority of OSCC patients (28/36) displayed evidence of high risk HPV positivity. Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established in HPV16 associated oropharyngeal cancer. These were involved in cell differentiation, proliferation and invasion and demonstrated considerable overlap with expression analysis data in other oncogenic pathways (SFRP1/CRCT1/DLG2/SYCP2/CRNN). SYCP2 showed the highest consistent fold change from baseline in both fresh frozen and FFPE tissue (qRT-PCR fresh frozen tissue [P<0.04]; FFPE tissue pre-invasive [P<0.01]; FFPE tissue invasive [P<0.01]), and aberrant expression of this meiosis-specific protein may contribute to genetic instability during HPV-associated cancer development. Conclusion: Investigation of differentially expressed genes in HPV-positive tumours may reveal unique pathways that can explain their different natural history and biological properties. The data from this study reveal SYCP2 (amongst others) as a potential biomarker in HPV positive oropharyngeal carcinoma, and if corroborated on a larger scale, may facilitate the development of a non-invasive screening tool.

Dataset Information

A novel variant of human Grb7 is associated with invasive esophageal carcinoma.

Publications

A novel variant of human Grb7 is associated with invasive esophageal carcinoma.

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