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Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas.

ABSTRACT: BACKGROUND:KIT is a proto-oncogene involved in diverse neoplastic processes. Aberrant kinase activity of the KIT receptor has been targeted by tyrosine kinase inhibitor (TKI) therapy in different neoplasias. In all the earlier studies, KIT expression was reported to be absent in meningiomas. However, we observed KIT mRNA expression in some meningioma cases. This prompted us to undertake its detailed analyses in meningioma tissues resected during 2008-2009. METHODS:Tumor tissues and matched peripheral blood samples collected from meningioma patients were used for detailed molecular analyses. KIT expression was ascertained immunohistochemically and validated by immunoblotting. KIT and KITLG transcript levels were discerned by reverse transcription quantitative real-time PCR (RT-qPCR). Similarly, KIT amplification and allele loss were assessed by quantitative real-time (qPCR) and validated by fluorescence in situ hybridization (FISH) on the neoplastic tissues. Possible alterations of the gene at the nucleotide level were analyzed by sequencing. RESULTS:Contrary to earlier reports, KIT expression, was detected immunohistochemically in 20.6% meningioma cases (n?=?34). Receptor (KIT) and ligand (KITLG) transcripts monitored by RT-qPCR were found to co-express (p?=?0.048) in most of the KIT immunopositive tumors. 1/7 KIT positive meningiomas showed allele loss corroborated by reduced FISH signal in the corresponding neoplastic tissue. Sequence analysis of KIT showed M541L substitution in exon 10, in one of the immunopositive cases. However, its biological consequence remains to be uncovered. CONCLUSIONS:This study clearly demonstrates KIT over-expression in the human meningiomas. The data suggest that up-regulated KIT transcription (p??0.05), is a likely mechanism responsible for altered KIT expression. Thus, KIT is a potential candidate for detailed investigation in the context of meningioma pathogenesis.

SUBMITTER: Saini M

PROVIDER: S-EPMC3443037 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas.

Saini Masum M Jha Ajaya Nand AN Abrari Andleeb A Ali Sher S

BMC cancer 20120606

<h4>Background</h4>KIT is a proto-oncogene involved in diverse neoplastic processes. Aberrant kinase activity of the KIT receptor has been targeted by tyrosine kinase inhibitor (TKI) therapy in different neoplasias. In all the earlier studies, KIT expression was reported to be absent in meningiomas. However, we observed KIT mRNA expression in some meningioma cases. This prompted us to undertake its detailed analyses in meningioma tissues resected during 2008-2009.<h4>Methods</h4>Tumor tissues an ...[more]

PMID: 22672386

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Project description:Background & aimsReceptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer.MethodsAn array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Cells were analyzed by real-time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis.ResultsKIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice compared with control cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5 associated genes. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Imatinib inhibited growth of KIT(+) colon cancer organoids in culture and growth of xenograft tumors in mice. Cancer cells with endogenous KIT expression were more tumorigenic in mice.ConclusionsKIT and KITLG are expressed by a subset of human colon tumors. KIT signaling promotes growth of colon cancer cells and organoids in culture and xenograft tumors in mice via its ligand, KITLG, in an autocrine or paracrine manner. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors.

Dataset Information

Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas.

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Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas.

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