Cancer

Esophageal squamous cell carcinomas; Lung squamous cell carcinomas; Glioblastoma; Non-small cell lung cancer (NSCLC)

PKCi may be an oncoprotein (OP). PKCi activity mediates the resistance of BCR-ABL transformed leukemia cells to apoptotic inducing drugs, thus the protein may play a role in cancer progression and cell survival through the inhibition of apoptosis. In glioblastoma cancer cell lines, PKCi acts downstream of PI3K as an anti-apoptotic factor through phosphorylation and inhibition of the pro-apoptotic factor BAD. In small-cell lung cancer cell lines, PKCi forms a protein complex with PARD6A and ECT2 which functions to positively regulate ECT2 oncogenic activity, thus promoting tumour growth and metastasis. In addition, the transformation and tumour progression of both lung and esophageal squamous cell carcinoma is associated with the amplification of the chromosomal region 3q26, which contains the PKCi, ECT2, PIK3CA, SOX2 and MDS1 genes, thus implicating PKCi in the progression of these cancers. Furthermore, elevated expression of PKCi in esophageal squamous cell carcinoma specimens was significantly correlated with tumour size, metastasis, and advanced stages of cancer progression. Similarly, PKCi over-expression in lung squamous cell carcinoma was associated with the maintenance of a stem-like phenotype of the cancer cells through cooperative action with SOX2 and influence on the sonic-hedgehog (Shh) signalling pathway. Therefore, PKCi is suggested to act as an oncoprotein in the development of several cancer types.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +109, p<0.014); Breast epithelial carcinomas (%CFC= -47, p<0.04); Cervical cancer (%CFC= -49, p<0.003); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +215, p<0.0001); Ovary adenocarcinomas (%CFC= +125, p<0.007); Prostate cancer - primary (%CFC= +95, p<0.0001); Skin squamous cell carcinomas (%CFC= +152, p<0.064). The COSMIC website notes an up-regulated expression score for PKCi in diverse human cancers of 1080, which is 2.3-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 27 for this protein kinase in human cancers was 0.5-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.09 % in 25377 diverse cancer specimens. This rate is only 24 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.74 % in 1093 large intestine cancers tested; 0.35 % in 805 skin cancers tested; 0.17 % in 1941 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R480C (10); R480H (3).

Six deletions (all at T276fs*7), 4 insertions (all at T276fs*16), and no complex mutations are noted on the COSMIC website. About 21% of the point mutations are silent and do not change the amino acid sequence of the protein kinase.