Meta-analysis of Oncogenic Protein Kinase Cι Signaling in Lung Adenocarcinoma

Abstract

Purpose Atypical protein kinase Cι (PKCι) is an oncogene in non – small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCι in lung adenocarcinoma (LAC), the most prominent form of NSCLC. Experimental Design Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCι in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediated knockdown of PKCι and the target genes was used to determine whether expression of the identified genes was regulated by PKCι, and whether these target genes play a role in anchorage-independent growth and invasion of LAC cells. Results Meta-analysis identified seven genes whose expression correlated with PKCι in primary LAC. Subsequent QPCR analysis confirmed coordinate overexpression of four genes (COPB2, ELF3, RFC4, and PLS1) in an independent set of LAC samples. RNAi-mediated knockdown showed that PKCι regulates expression of all four genes in LAC cells, and that the four PKCι target genes play an important role in the anchorage-independent growth and invasion of LAC cells. Meta-analysis of gene expression data sets from lung squamous cell, breast, colon, prostate, and pancreas carcinomas, as well as glioblastoma, revealed that a subset of PKCι target genes, particularly COPB2 and RFC4, correlate with PKCι expression in many tumor types. Conclusion Meta-analysis of public gene expression data are useful in identifying novel gene targets of oncogenic PKCι signaling. Our data indicate that both common and cell type – specific signaling mechanisms contribute to PKCι-dependent transformation.

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

“…However, SOX2 is a LSCC-specific stem factor that is not highly expressed in LADC (Tatsumori et al, 2014; Yuan et al, 2010) suggesting that another transcription factor(s) may be targeted by PKCι in KRAS LADC oncospheres. In a meta-analysis, we identified four genes whose expression correlates with PKCι in multiple LADC gene expression datasets (Erdogan et al, 2009). Among these genes was ELF3 , an ETS family transcription factor implicated in lung epithelial stem cell maintenance (Oliver et al, 2011).…”

Protein Kinase C (PKC) Isozymes and Cancer

“…In this process, MMP-10 acts as a critical effector of the PKC -Par6/Rac1 signaling axis that is required for anchorage-independent growth and invasion of NSCLC cells [313]. In PKC -dependent adenocarcinoma transformation, PKC induces four target genes, COPB2, ELF3, RFC4, and PLS1, whose expression has been correlated with PKC activity [314]. Therefore, overexpression of PKC is connected with poor survival in patients with NSCLC and can be used as a prognostic indicator [306].…”

Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma

“…Mining of public data has proved a useful approach in cancer research [40][41][42] . We found that the gene expression pattern of FST varied among the 149 clinical synovial samples The relative expression levels of FST mRNA and FST-correlated genes were determined in tissue samples from 149 patients with synovial sarcoma by meta-analysis; (Spearman r>0.6, P<0.001).…”