Dataset Information

Targeted Quantitative Kinome Analysis Identifies PRPS2 as a Promoter for Colorectal Cancer Metastasis.

ABSTRACT: Kinases are among the most important families of enzymes involved in cell signaling. In this study, we employed a recently developed parallel-reaction monitoring (PRM)-based targeted proteomic method to examine the reprogramming of the human kinome during colorectal cancer (CRC) metastasis. We were able to quantify the relative expression of 299 kinase proteins in a pair of matched primary/metastatic CRC cell lines. We also found that, among the differentially expressed kinases, phosphoribosyl pyrophosphate synthetase 2 (PRPS2) promotes the migration and invasion of cultured CRC cells through regulating the activity of matrix metalloproteinase 9 (MMP-9) and the expression of E-cadherin. Moreover, we found that the up-regulation of PRPS2 in metastatic CRC cells could be induced by the MYC proto-oncogene. Together, our unbiased kinome profiling approach led to the identification, for the first time, of PRPS2 as a promoter for CRC metastasis.

SUBMITTER: Miao W

PROVIDER: S-EPMC6499697 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Targeted Quantitative Kinome Analysis Identifies PRPS2 as a Promoter for Colorectal Cancer Metastasis.

Miao Weili W Wang Yinsheng Y

Journal of proteome research 20190402 5

Kinases are among the most important families of enzymes involved in cell signaling. In this study, we employed a recently developed parallel-reaction monitoring (PRM)-based targeted proteomic method to examine the reprogramming of the human kinome during colorectal cancer (CRC) metastasis. We were able to quantify the relative expression of 299 kinase proteins in a pair of matched primary/metastatic CRC cell lines. We also found that, among the differentially expressed kinases, phosphoribosyl p ...[more]

PMID: 30908912

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Project description:PurposeTriple-negative breast cancer (TNBC) does not have defined therapeutic targets and is currently treated with chemotherapy only. Kinase dysregulation triggers cancer cell proliferation and metastasis and is a crucial therapeutic target for cancer. In this study, targeted kinome sequencing of TNBC tumors was performed to assess the association between kinome gene alterations and disease outcomes in TNBC.MethodsA kinome gene panel consisting of 612 genes was used for the targeted sequencing of 166 TNBC samples and matched normal tissues. Analyses of the significantly mutated genes were performed. Genomic differences between Asian and non-Asian patients with TNBC were evaluated using two Asian TNBC datasets (from Seoul National University Hospital [SNUH] and Fudan University Shanghai Cancer Center [FUSCC]) and three non-Asian TNBC datasets (The Cancer Genome Atlas [TCGA], METABRIC, and Gustave Roussy). The prognostic value of kinome gene mutations was evaluated using tumor mutational burden (TMB) and oncogenic pathway analyses. Mutational profiles from the TCGA were used for validation.ResultsThe significantly mutated genes included TP53 (60% of patients), PIK3CA (21%), BRCA2 (8%), and ATM (8%). Compared with data from non-Asian public databases, the mutation rates of PIK3CA p.H1047R/Q were significantly higher in the SNUH cohort (p = 0.003, 0.048, and 0.032, respectively). This was verified using the FUSCC dataset (p = 0.003, 0.078, and 0.05, respectively). The TMB-high group showed a trend toward longer progression-free survival in our cohort and the TCGA TNBC cohort (p = 0.041 and 0.195, respectively). Kinome gene alterations in the Wnt pathway in patients with TNBC were associated with poor survival in both datasets (p = 0.002 and 0.003, respectively).ConclusionComprehensive analyses of kinome gene alterations in TNBC revealed genomic alterations that offer therapeutic targets and should help identify high-risk patients more precisely in future studies.

Project description:MACC1, Metastasis associated in colon cancer 1, is a newly identified prognostic biomarker for colorectal cancer metastasis and patient survival, when determined in the primary tumor or patient blood. MACC1 induces cell motility and proliferation in cell culture and metastasis in mouse models. MACC1 acts as a transcriptional regulator of the receptor tyrosine kinase gene Met via binding to its promoter. However, no information about the promoter of the MACC1 gene and its transcriptional regulation has been reported so far. Here we report the identification of the MACC1 promoter using a promoter luciferase construct that directs transcription of MACC1. To gain insights into the essential domains within this promoter region, we constructed 5' truncated deletion constructs. Our results show that the region from -426 to -18 constitutes the core promoter and harbors functional motifs for the binding of AP-1, Sp1, and C/EBP transcription factors as validated by site directed mutagenesis study. Using electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we demonstrated the physical interaction of these transcription factors to a minimal essential MACC1 core promoter sequence. Knock down of these transcription factors using RNAi strategy reduced MACC1 expression (P < 0.001), and resulted in decrease of cell migration (P < 0.01) which could be specifically rescued by ectopic overexpression of MACC1. In human colorectal tumors, expression levels of c-Jun and Sp1 correlated significantly to MACC1 (P = 0.0007 and P = 0.02, respectively). Importantly, levels of c-Jun and Sp1 also showed significant correlation to development of metachronous metastases (P = 0.01 and P = 0.001, respectively). This is the first study identifying the MACC1 promoter and its transcriptional regulation by AP-1 and Sp1. Knowledge of the transcriptional regulation of the MACC1 gene will implicate in enhanced understanding of its role in cancer progression and metastasis.

Dataset Information

Targeted Quantitative Kinome Analysis Identifies PRPS2 as a Promoter for Colorectal Cancer Metastasis.

Publications

Targeted Quantitative Kinome Analysis Identifies PRPS2 as a Promoter for Colorectal Cancer Metastasis.

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