Gene Summary

Gene:PRKCA; protein kinase C alpha
Aliases: AAG6, PKCA, PRKACA, PKCI+/-, PKCalpha, PKC-alpha
Summary:Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been reported to play roles in many different cellular processes, such as cell adhesion, cell transformation, cell cycle checkpoint, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein kinase C alpha type
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PRKCA (cancer-related)

Coppé JP, Mori M, Pan B, et al.
Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities.
Nat Cell Biol. 2019; 21(6):778-790 [PubMed] Related Publications
Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAF

Kaowinn S, Oh S, Moon J, et al.
CGK062, a small chemical molecule, inhibits cancer upregulated gene 2‑induced oncogenesis through NEK2 and β‑catenin.
Int J Oncol. 2019; 54(4):1295-1305 [PubMed] Free Access to Full Article Related Publications
The mechanisms through which cancer‑upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/β‑catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of β‑catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of β‑catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of β‑catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased β‑catenin expression and activity. The suppression of β‑catenin decreased cancer stem cell (CSC)‑like phenotypes, indicating that β‑catenin is involved in CUG2‑mediated CSC‑like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of β‑catenin at Ser33/Ser37, which is known to recruit E3 ligase for β‑catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A‑related kinase 2 (NEK2). Recombinant NEK2 phosphorylated β‑catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of β‑catenin, suggesting that NEK2 is involved in the phosphorylation of β‑catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of β‑catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced β‑catenin levels and inhibited the CUG2‑induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2‑mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of β‑catenin at Ser33/Ser37 by activating NEK2, thus stabilizing β‑catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2‑overexpressing lung cancer cells.

He C, Sun J, Liu C, et al.
Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.
Clin Epigenetics. 2019; 11(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS.
RESULTS: First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and KDM6B that were upregulated after cisplatin treatment. Consistent with the clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, we evaluated the effects of H3K27me3 alteration on OS chemosensitivity. In vitro inhibition of the histone methyltransferase EZH2 in OS cells decreased H3K27me3 levels and led to cisplatin resistance. Conversely, inhibition of the demethylases KDM6A and KDM6B increased H3K27me3 levels in OS and reversed cisplatin resistance in vitro and in vivo. Mechanistically, with the help of RNA sequencing (RNAseq), we found that PRKCA and MCL1 directly participated in the process by altering H3K27me3 on their gene loci, ultimately inactivating RAF/ERK/MAPK cascades and decreasing phosphorylation of BCL2.
CONCLUSIONS: Our study reveals a new epigenetic mechanism of OS resistance and indicates that elevated H3K27me3 levels can sensitize OS to cisplatin, suggesting a promising new strategy for the treatment of OS.

Brix DM, Tvingsholm SA, Hansen MB, et al.
Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion.
Oncogene. 2019; 38(17):3170-3184 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.

Matsukuma KE, Yeh MM
Update on the pathology of liver neoplasms.
Ann Diagn Pathol. 2019; 38:126-137 [PubMed] Related Publications
Many advances have developed in the pathology of liver tumors in the recent decade. Examples of these advances include the use of glutamine synthetase in the diagnosis of focal nodular hyperplasia, subtyping of hepatocellular adenomas using molecular and immunohistochemical methods, the unraveling of the fusion transcript between the DNAJB1 gene and the PRKACA gene in fibrolamellar carcinoma, and the more unified classification and terminology in intrahepatic bile duct tumors and their precursor lesions. Nevertheless, challenges still remain, e.g., the differential diagnosis between well-differentiated hepatocellular carcinoma and hepatocellular adenoma; distinction among poorly differentiated hepatocellular carcinoma, cholangiocarcinoma and metastatic neoplasm; terminology of the combined hepatocellular carcinoma-cholangiocarcinoma, etc. This review aims to address updates in the pathologic diagnosis and clinical relevance of tumors of the liver and intrahepatic bile ducts in adults and their differential diagnosis and diagnostic pitfalls.

Li HY, Yang S, Li JC, Feng JX
Galectin 3 inhibition attenuates renal injury progression in cisplatin-induced nephrotoxicity.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Nephrotoxicity is a major toxic effect in chemotherapy, which constitutes up to 60% of hospitalized acute kidney injury (AKI). Very few treatment options exist to slow the transition from AKI to subsequent chronic kidney diseases (CKD). Here, we demonstrate that galectin-3 (Gal-3), a β-galactoside binding lectin that plays an important role in kidney fibrosis and renal failure, is one of the key factors for renal injury progression. Ectopic overexpression of Gal-3 significantly decreased the viability of HEK293, simultaneously inducing of cell cycle arrest and apoptosis. However, inhibition of Gal-3, mediated by modified citrus pectin (MCP), predominantly antagonized the pro-apoptotic effects. Mice were pre-treated with normal or 1% MCP-supplemented drinking water 1 week before cisplatin injection. Analyses of serum creatinine and renal tissue damage indicated that MCP-treated mice demonstrated increased renal function and attenuated renal fibrosis after cisplatin-induced injury. MCP-treated mice also demonstrated decreased renal fibrosis and apoptosis, as revealed by masson trichrome staining and Western blot analysis of cleaved caspase-3. Additionally, the protective role of Gal-3 inhibition in the kidney injury was shown to be mediated by protein kinase C α (PKC-α), which promoted cell apoptosis and collagen I synthesis in HEK293 cells. These results demonstrated the potential Gal-3 and PKC-α as therapeutic targets for the treatment of AKI and CKD.

Li Y, Luan C
Yonsei Med J. 2018; 59(10):1159-1165 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: To investigate the effect and mechanism of phospholipase C epsilon gene 1 (
MATERIALS AND METHODS: The esophageal carcinoma cell lines Eca109 and EC9706 and normal esophageal epithelial cell line HEEC were cultured. The expression of PLCE1, protein kinase C alpha (PKCα), and nuclear factor kappa B (NF-κB) p50/p65 homodimer in cells were comparatively analyzed. The esophageal cancer cells were divided into si-PLCE1, control siRNA (scramble), and mock groups that were transfected with specific siRNA for PLCE1, control siRNA, and blank controls, respectively. Expression of PLCE1, PKCα, p50, and p65 was detected by Western blotting. Transwell assay was used to detect migration and invasion of Eca109 and EC9706 cells.
RESULTS: Compared with HEEC, the expression of PLCE1, PKCα, p50, and p65 was increased in Eca109 and EC9706 cells. The expression of PLCE1 was positively correlated with the expression of PKCα and p50 (PKCα: r=0.6328,
CONCLUSION: PLCE1 activated NF-κB signaling by up-regulating PKCα, which could promote invasion and migration of esophageal cancer cells.

Bing Z, Cheng Z, Shi D, et al.
Investigate the mechanisms of Chinese medicine Fuzhengkangai towards EGFR mutation-positive lung adenocarcinomas by network pharmacology.
BMC Complement Altern Med. 2018; 18(1):293 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Chinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients. However, the pharmacological and molecular mechanisms underlying the active ingredients, potential targets, and overcome drug resistance of the drug are still unclear. Therefore, it is necessary to explore the molecular mechanism of FZKA.
METHODS: A systems pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of EGFR-TKI resistance with clinically effective herb formula. The differential gene expressions between EGFR-TKI sensitive and resistance cell lines were calculated and used to find overlap from targets as core targets. The prognosis of core targets was validated from the cancer genome atlas (TCGA) database by Cox regression. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment is applied to analysis core targets for revealing mechanism in biology.
RESULTS: The results showed that 35 active compounds of FZKA can interact with eight core targets proteins (ADRB2, BCL2, CDKN1A, HTR2C, KCNMA1, PLA2G4A, PRKCA and LYZ). The risk score of them were associated with overall survival and relapse free time (HR = 6.604, 95% CI: 2.314-18.850; HR = 5.132, 95% CI: 1.531-17.220). The pathway enrichment suggested that they involved in EGFR-TKI resistance and non-small cell lung cancer pathways, which directly affect EGFR-TKI resistance. The molecular docking showed that licochalcone a and beta-sitosterol can closely bind two targets (BCL2 and PRKCA) that involved in EGFR-TKI resistance pathway.
CONCLUSIONS: This study provided a workflow for understanding mechanism of CHM for against drug resistance.

Huang Y, Huang Y, Zhang L, et al.
Identification of crucial genes and prediction of small molecules for multidrug resistance of Hodgkin's lymphomas.
Cancer Biomark. 2018; 23(4):495-503 [PubMed] Related Publications
BACKGROUND: Multidrug resistance of Hodgkin's lymphoma (HL) often results in recurrence. Thus, we aimed to explore the underlying molecular mechanisms of multidrug resistance using bioinformatics strategies.
METHODS: The gene expression profile was obtained from GEO database. Then, the differentially expressed genes were screened out, and their functional annotations were carried out. Then, gene-signal interaction network was constructed and Connectivity Map (CMAP) analysis was performed.
RESULTS: A total of 1425 dysregulated genes were screened out, which were mainly enriched in biological items, such as small molecule metabolic, signal transduction, and cell apoptosis. Some survival-related pathways, such as MAPK pathways, apoptosis, and P53 pathway, and several hub genes, such as PRKCA, ACTN1, PIP5K1B, PRKACB, and JAK2, might play key roles in the development of multidrug resistance. Interestingly, felodipine was predicted to be a potential agent overcoming the multidrug resistance.
CONCLUSIONS: The present study offered new insights into the molecular mechanisms of multidrug resistance and identified a series of important hub genes and small agents that might be critical for treatment of multidrug-resistant HL.

Yuan M, Yuan J, Mei L, Abulizi G
Bioinformatics analysis of methylation in cervical adenocarcinoma in Xinjiang, China.
Medicine (Baltimore). 2018; 97(35):e12108 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
This study is to investigate the genomic methylation in cervical adenocarcinoma in Xinjiang, China, using the DNA methylation analysis chips.Methylation of 5 cases of cervical adenocarcinoma tissues and 5 cases of normal cervical tissues were analyzed by the Illumina 850K methylation chip. The genes with abnormal methylation modification were screened out and analyzed by the gene ontology (GO) functional annotation analysis. Enrichment analysis of kyoto encyclopedia of genes and genomes (KEGG) signal transduction pathways was also performed.Totally 4056 sites showed differential expression patterns in cervical adenocarcinoma tissues compared to normal cervical tissues, of which 3738 were hypermethylated, and 318 were hypomethylated. The distribution of these sites covered from the 1st to 22nd chromosomes. GO functional annotation analysis showed that the differentially expressed genes in cervical adenocarcinoma tissues were mainly involved in the processes of tumor growth, development, metabolism, ion transport, transcriptional regulation, cell division, cell cycle regulation, and signal transduction. KEGG signaling pathway analysis showed that the most significantly different signaling pathway was the neuroactive ligand-receptor interaction. Gene-net-work analysis suggested that CCND1, CTNNB1, MAPK10, and PRKCA were involved.Methylated genes are specifically expressed in cervical adenocarcinoma tissues in Xinjiang, China. Four of these genes (CCND1, CTNNB1, MAPK10, and PRKCA) with differential expression patterns may play important regulatory roles in cervical adenocarcinoma development through affecting the neuroactive ligand-receptor interaction.

Barritault M, Meyronet D, Ducray F
Molecular classification of adult gliomas: recent advances and future perspectives.
Curr Opin Oncol. 2018; 30(6):375-382 [PubMed] Related Publications
PURPOSE OF REVIEW: This review summarizes recent advances in the molecular classification of adult gliomas.
RECENT FINDINGS: According to the 2016 WHO classification, five main molecular subgroups of adult diffuse gliomas can be distinguished based on the 1p/19q codeletion, isocitrate dehydrogenase (IDH), and histone H3.3 mutation status. In the future, this classification may be further refined based on the integration of additional biomarkers, in particular CDKN2A/B homozygous deletion in IDH-mutant astrocytomas, TERT promoter mutations, EGFR amplification, chromosome 7 gain and chromosome 10 loss in IDH-wildtype astrocytomas, and FGFR1 mutations in midline gliomas. Histone H3.3 G34R/V defines a distinct subgroup of hemispheric IDH-wildtype high-grade gliomas occurring in young patients and FGFR gene fusions characterize a subgroup of IDH-wildtype glioblastomas that could benefit from specific treatment approaches. RNA sequencing may identify targetable gene fusions in circumscribed gliomas lacking classical BRAF alterations. In chordoid gliomas, recurrent PRKCA mutations could serve as a new diagnostic marker. Among comprehensive molecular analysis methods, DNA methylation profiling appears as a particularly powerful approach to identify new molecular subgroups of gliomas and to classify difficult cases.
SUMMARY: The classification of adult gliomas may be improved by the integration of additional biomarkers and/or by comprehensive molecular analysis, in particular DNA methylation profiling. The most relevant approach, however, remains to be established.

Kim SJ, Pham TH, Bak Y, et al.
7-Methoxy-luteolin-8-C-β-6-deoxy-xylo-pyranos-3-uloside exactly (mLU8C-PU) isolated from Arthraxon hispidus inhibits migratory and invasive responses mediated via downregulation of MMP-9 and IL-8 expression in MCF-7 breast cancer cells.
Environ Toxicol. 2018; 33(11):1143-1152 [PubMed] Related Publications
7-Methoxy-luteolin-8-C-β-6-deoxy-xylo-pyranos-3-uloside (mLU8C-PU) is a glycosylflavone of luteolin isolated from Arthraxon hispidus (Thunb.). Luteolin is known to exert anti-migratory and anti-invasive effects on tumor cells. However, there are no reports on the effects of mLU8C-PU on tumor invasiveness and associated signaling pathways. In this study, we demonstrated the anti-migratory and anti-invasive effects of mLU8C-PU in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 breast cancer cells. We also investigated the effect of mLU8C-PU on invasion- related signal transducers, including protein kinase Cα (PKCα), c-Jun N terminal kinase (JNK), activator protein-1 (AP-1), and nuclear factor-kappa B (NF-ĸB). TPA-induced membrane translocation of PKCα, phosphorylation of JNK, and the nuclear translocations of AP-1 and NF-κB were downregulated by mLU8C-PU in MCF-7 cells. In addition, mLU8C-PU also inhibited matrix metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) expression. These results indicate that mLU8C-PU inhibits migratory and invasive responses in MCF-7 breast cancer cells by suppressing MMP-9 and IL-8 expression through mitigating TPA-induced PKCα, JNK activation, and the nuclear translocation of AP-1 and NF-κB. These results suggest that mLU8C-PU may be used as an anti-metastatic agent.

Arun A, Ansari MI, Popli P, et al.
New piperidine derivative DTPEP acts as dual-acting anti-breast cancer agent by targeting ERα and downregulating PI3K/Akt-PKCα leading to caspase-dependent apoptosis.
Cell Prolif. 2018; 51(6):e12501 [PubMed] Related Publications
OBJECTIVES: In our ongoing studies to develop ER targeting agents, we screened for dual-acting molecules with a hypothesis that a single molecule can also target both ER positive and negative groups of breast cancer.
MATERIALS AND METHODS: 1-(2-(4-(Dibenzo[b,f]thiepin-10-yl)phenoxy)ethyl)piperidine (DTPEP) was synthesized and screened in both MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) cells. Assays for analysis of cell cycle, ROS, apoptosis and MMP loss were carried out using flow cytometry. Its target was investigated using western blot, transactivation assay and RT-PCR. In vivo efficacy of DTPEP was validated in LA-7 syngeneic rat mammary tumour model.
RESULTS: Here, we report identification of dual-acting molecule DTPEP that downregualtes PI3K/Akt and PKCα expression, induces ROS and ROS-dependent apoptosis, loss of mitochondrial membrane potential, induces expression of caspase indicative of both intrinsic and extrinsic apoptosis in MCF-7 and MDA-MB-231 cells. In MCF-7 cells, DTPEP downregulates ERα expression and activation. In MDA-MB-231 cells, primary cellular target of DTPEP is not clearly known, but it downregualtes PI3K/Akt and PKCα expression. In vivo study showed regression of LA-7 syngeneic mammary tumour in SD rat.
CONCLUSIONS: We identified a new dual-acting anti-breast cancer molecules as a proof of concept which is capable of targeting both ER-positive and ER-negative breast cancer.

Naveen Kumar M, Babu RL, Patil RH, et al.
Protein kinases orchestrate cell cycle regulators in differentiating BeWo choriocarcinoma cells.
Mol Cell Biochem. 2019; 452(1-2):1-15 [PubMed] Related Publications
Choriocarcinoma, a trophoblastic neoplasia, occurs in women as an incidence of abnormal pregnancy. BeWo choriocarcinoma cells derived from the abnormal placentation are a suitable model system to study the factors associated with differentiation, invasion and other cellular events as an alternative to clinical samples. Many protein kinases orchestrate the complex events of cell cycle and in case of malignancy such regulators are found to be mutated. In the present study, BeWo cells treated with forskolin (Fo) and phorbol 12-myristate 13-acetate (PMA) were used to study the role of PKA (protein kinase A) and PKC (protein kinase C), respectively, on the expression pattern of differentiation-related genes, membrane markers, PKC isoforms and cell cycle regulators. The effect of Fo and PMA on the cell proliferation was assessed. Progressive induction of alkaline phosphatase level and formation of multinucleated differentiated cells were observed in the cells treated with Fo. Exposure of cells to Fo and PMA induced the mRNA transcripts of α-hCG, β-hCG and endoglin and down-regulates E-cadherin at mRNA and protein levels. Synergistic levels of both up- and down-regulated genes/proteins were observed when cells were treated with the combination of Fo and PMA. The mRNA levels of cyclin D1, cyclin E1, p21, Rb, p53, caspase-3 and caspase-8 decreased gradually during differentiation. Fo significantly inhibited the protein levels of PCNA, Rb, PKC-α and PMA stimulated mRNA expression of PKC-ε and PKC-δ. Further, failure in the activation of essential components of the cell cycle machinery caused G2/M phase arrest in differentiating BeWo cells.

Kayser K, Degenhardt F, Holzapfel S, et al.
Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes.
Int J Cancer. 2018; 143(11):2800-2813 [PubMed] Related Publications
In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.

Weigand I
Pathogenesis of benign unilateral adrenocortical tumors: focus on cAMP/PKA pathway.
Minerva Endocrinol. 2019; 44(1):25-32 [PubMed] Related Publications
Somatic mutations affecting genes in the cAMP/PKA (protein kinase A) signaling pathway have been described as causative for the pathogenesis of benign unilateral adrenocortical adenomas associated with cortisol over secretion. These include predominantly somatic mutations in the PRKACA gene which encodes the catalytic subunit α of PKA. In addition, mutations in the GNAS gene, coding for the stimulatory G protein α, have been observed in approximately 10% of cortisol producing adenomas (CPA). The mutations render PKA signaling constitutively active and are therefore involved in cortisol over secretion of these tumors. Despite the prominent role of the cAMP/PKA pathway in the pathogenesis of unilateral CPA, also mutations in the CTNNB1 gene, encoding β-catenin, were identified in CPA. However, mutations in β-catenin are not limited to CPA and are not associated with cortisol secretion since they were predominantly found in endocrine-inactive adenomas (EIA) and might hence contribute to tumorigenesis in adrenocortical tissues. In this review, recent findings in the pathogenesis of benign adrenocortical tumors with a particular focus on the cAMP/PKA signaling pathway are summarized.

Gong S, Xu D, Zhu J, et al.
Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells.
Cell Physiol Biochem. 2018; 47(2):680-693 [PubMed] Related Publications
BACKGROUND/AIMS: Mutations in the Ras/Raf/MEK/ERK pathway are detected in 50% of colorectal cancer cases and play a crucial role in cancer development and progression. Cobimetinib is a MEK inhibitor approved for the treatment of advanced melanoma and inhibits the cell viability of other types of cancer cells.
METHODS: HCT116 colorectal cancer cells were treated with cobimetinib, and MTT assay, colony formation assay, and flow cytometry were used to evaluate cell viability, cell cycle, and apoptosis, respectively. The expression of genes associated with the cell cycle and apoptosis were evaluated by quantitative real-time PCR and western blotting. To explore use of cobimetinib in colorectal cancer treatment and further understand its mechanisms, RNA-seq technology was used to identify differentially expressed genes (DEGs) between cobimetinib-treated and untreated HCT116 cells. Furthermore, we compared these DEGs with Gene Expression Omnibus data from colorectal cancer tissues and normal colonic epithelial tissues.
RESULTS: We found that cobimetinib not only inhibited cell proliferation but also induced G1 phase arrest and apoptosis in HCT116 colorectal cancer cells, suggesting that cobimetinib may useful in colorectal cancer therapy. After cobimetinib treatment, 3,495 DEGs were obtained, including 2,089 upregulated genes and 1,406 downregulated genes, and most of these DEGs were enriched in the cell cycle, DNA replication, and DNA damage repair pathways. Our results revealed that some genes with high expression in colorectal cancer tissues were downregulated by cobimetinib in HCT116 cells, including CCND1, E2F1, CDC25C, CCNE2, MYC, and PCNA. These genes have vital roles in DNA replication and the cell cycle. Furthermore, genes with low expression in colorectal cancer tissues were upregulated by cobimetinib, including PRKCA, PI3K, RTK, and PKC. Based on our results, the PKC and PI3K pathways were activated after cobimetinib treatment, and inhibition of these two pathways can increase the cytotoxicity of cobimetinib in HCT116 cells. Notably, cobimetinib appeared to enhance the efficacy of 5-fluorouracil (5-FU) by decreasing TYMS expression, high expression of which is responsible for 5-FU resistance in colorectal cancer.
CONCLUSIONS: Our results suggest the potential use of cobimetinib in colorectal cancer therapy.

Liu B, Tan J, Wang X, Liu X
Identification of recurrent risk-related genes and establishment of support vector machine prediction model for gastric cancer.
Neoplasma. 2018; 65(3):360-366 [PubMed] Related Publications
This study sought to investigate genes related to recurrent risk and establish a support vector machine (SVM) classifier for prediction of recurrent risk in gastric cancer (GC).Based on the gene expression profiling dataset GSE26253, feature genes that were significantly associated with survival time and status were screened out. Subsequently, protein-protein interaction (PPI) network was constructed for these feature genes, and genes in this network was optimized using betweenness centrality algorithm in order to identify genes potentially correlated with GC (named as GCGs). In total, 1202 feature genes were identified to be significantly associated with survival time and status of GC, among of which, 65 genes were identified as a classifier that was able to recognize recurrence and nonrecurrence GC cases with a high sensitivity and specificity, predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUC). Furthermore, the classifier was able to reasonably classify tumor samples in GSE15459 into high and low recurrent risk groups. Among those genes, a set of genes were predicted to have interactions (e.g. RHOA interacting with TGFBR1, PRKACA and PLCG1; TGFBR1 interacting with TGFBR2) and be involved in pathways like MAPK signaling (e.g. TGFBR1 and TGFBR2), adherens junction (e.g. RHOA) and apoptosis (e.g. PRKACA).The genes in the classifier model may be related to GC recurrence, and the classifier model may contribute to the prediction of recurrent risk in GC.

Graham RP
Fibrolamellar Carcinoma: What Is New and Why It Matters.
Surg Pathol Clin. 2018; 11(2):377-387 [PubMed] Related Publications
Fibrolamellar carcinoma is distinctive at clinical and histologic levels. A novel DNAJB1-PRKACA fusion gene characterizes almost all cases, distinguishes it from other hepatocellular neoplasms, and drives the pathogenesis of this unique tumor. A subset of cases of fibrolamellar carcinoma is associated with alternate mechanisms of protein kinase A activation. This review article discusses common and unusual histologic features of fibrolamellar carcinoma, its differential diagnoses, and how to make the diagnosis while avoiding key pitfalls. The impact of the discovery of the fusion gene on the understanding of the tumor and the prognosis of fibrolamellar carcinoma are also discussed.

Assié G
Genomic insights into Cushing syndrome.
Ann Endocrinol (Paris). 2018; 79(3):119-122 [PubMed] Related Publications
In the setting of Cushing syndrome, genomic analyses can be performed either in tumors responsible for endogenous Cushing, or in patients exposed to glucocorticoid excess. Genomics of tumors identified several new genes - including ZNRF3 in adrenocortical carcinomas, PRKACA in cortisol-producing adrenal adenomas, ARMC5 in primary macronodular adrenal hyperplasia and USP8 in pituitary corticotroph adenomas. These genes shed new lights on the mechanisms responsible for these tumors. Integrated genomic studies of adrenal carcinomas identified distinct molecular classes, with remarkably different prognostic outcome. Beyond the mechanistic novelties, a new generation of prognostic markers emerges, with potentially important impact on patients care. For the future, genomic efforts should be pursued, focusing on poorly characterized tumors responsible for Cushing syndrome - including endocrine tumors secreting ACTH. In addition, epigenomics is emerging as an outstanding set of tools for characterizing tumors, unraveling unprecedented aspects of tumorigenesis. Applying these tools to endocrine tumors responsible for Cushing syndrome may also lead to important discoveries. Genomics of patients exposed to glucocorticoid excess is an emerging research field. Proof of principle studies have been performed, identifying molecular markers of glucocorticoid excess in blood. Research efforts should now concentrate on markers of mild glucocorticoid excesses - endogenous or exogenous -, owing to their high prevalence in general population. In addition, markers of individual susceptibility to each type of glucocorticoid complication are needed. It remains to be determined whether genomics can identify such markers.

Siegfried A, Rousseau A, Maurage CA, et al.
EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity.
Brain Pathol. 2019; 29(1):53-62 [PubMed] Related Publications
We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N-terminal transcriptional activation domain of EWSR1 gene and the C-terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF

Lalazar G, Simon SM
Fibrolamellar Carcinoma: Recent Advances and Unresolved Questions on the Molecular Mechanisms.
Semin Liver Dis. 2018; 38(1):51-59 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of primary liver cancer that affects adolescents and young adults without underlying liver disease. Surgery remains the mainstay of therapy; however, most patients are either not surgical candidates or suffer from recurrence. There is no approved systemic therapy and the overall survival remains poor. Historically classified as a subtype of hepatocellular carcinoma (HCC), FLC has a unique clinical, histological, and molecular presentation. At the genomic level, FLC contains a single 400kB deletion in chromosome 19, leading to a functional DNAJB1-PRKACA fusion protein. In this review, we detail the recent advances in our understanding of the molecular underpinnings of FLC and outline the current knowledge gaps.

Zhang C, Shen Y, Wang J, et al.
Identification of key pathways and genes in Barrett's esophagus using integrated bioinformatics methods.
Mol Med Rep. 2018; 17(2):3069-3077 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Barrett's esophagus (BE) is a premalignant lesion of esophageal adenocarcinoma. The aim of the present study was to investigate the possible mechanisms and biomarkers of BE. To identify the differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) in BE, the miRNA expression profile GSE20099 and the gene expression profiles GSE26886, GSE13083 and GSE34619 were obtained from the Gene Expression Omnibus (GEO) database. DEGs and DEmiRNAs were screened for using the GEO2R tool. Using DAVID, functional and pathway enrichment analysis was performed to explore the biological function of identified DEGs. The protein‑protein interaction (PPI) network was detected using STRING and constructed by Cytoscape software. Furthermore, targets of identified DEmiRNAs were predicted by the miRecords database, then integrated with the identified DEGs to obtain key genes involved in BE. In total, 311 DEGs were identified. These genes were significantly enriched in the pancreatic secretion, metabolic pathways and cytochrome P450 drug metabolism pathways. In the PPI network, 16 hub genes, including keratin 16, cystic fibrosis transmembrane conductance regulator, involucrin, protein kinase C α and cadherin 17 were identified. Following integration of the predicted target genes of DEmiRNAs with DEGs, three key BE genes were identified: PRKCA, CDH17 and epiregulin. In conclusion, a comprehensive bioinformatics analysis of identified DEGs and DEmiRNAs was performed to elucidate potential pathways and biomarkers involved in the development of BE.

Bonnet-Serrano F, Bertherat J
Genetics of tumors of the adrenal cortex.
Endocr Relat Cancer. 2018; 25(3):R131-R152 [PubMed] Related Publications
This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of

Graham RP, Lackner C, Terracciano L, et al.
Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion.
Hepatology. 2018; 68(4):1441-1447 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Fibrolamellar carcinomas are characterized by activation of protein kinase A, a kinase composed of catalytic and regulatory subunits. PRKACA encodes a catalytic subunit of protein kinase A, and almost all fibrolamellar carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting DNAJB1-PRKACA fusion transcript is believed to activate protein kinase A by dysregulation of the catalytic portion of the protein. In contrast, PRKAR1A encodes one of the regulatory subunits of protein kinase A. We hypothesized that loss of function of this regulatory unit could also lead to protein kinase A activation and thus to fibrolamellar carcinoma. Because PRKAR1A mutations underlie the Carney complex, we searched for liver tumors in individuals with the Carney complex. We identified 3 individuals with fibrolamellar carcinomas and a personal history of the Carney complex. All three tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for arginase, cytokeratin 7, and cluster of differentiation 68. Fluorescence in situ hybridization was negative for PRKACA rearrangements. However, PRKAR1A sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all three cases were negative for PRKAR1A protein expression, consistent with inactivation of this key regulatory unit of protein kinase A. We also identified one additional fibrolamellar carcinoma in an individual without a documented history of the Carney complex who was negative for PRKACA rearrangements but had loss of PRKAR1A protein expression as well as PRKAR1A mutations.
CONCLUSION: Fibrolamellar carcinoma can be part of the Carney complex; in this setting, fibrolamellar carcinomas have inactivating PRKAR1A mutations instead of the DNAJB1-PRKACA fusion gene found in sporadic fibrolamellar carcinomas, providing an alternate means for activation of protein kinase A. (Hepatology 2017).

Pham TND, Perez White BE, Zhao H, et al.
Protein kinase C α enhances migration of breast cancer cells through FOXC2-mediated repression of p120-catenin.
BMC Cancer. 2017; 17(1):832 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Despite recent advances in the diagnosis and treatment of breast cancer, metastasis remains the main cause of death. Since migration of tumor cells is considered a prerequisite for tumor cell invasion and metastasis, a pressing goal in tumor biology has been to elucidate factors regulating their migratory activity. Protein kinase C alpha (PKCα) is a serine-threonine protein kinase implicated in cancer metastasis and associated with poor prognosis in breast cancer patients. In this study, we set out to define the signaling axis mediated by PKCα to promote breast cancer cell migration.
METHODS: Oncomine™ overexpression analysis was used to probe for PRKCA (PKCα) and FOXC2 expression in mRNA datasets. The heat map of PRKCA, FOXC2, and CTNND1 were obtained from the UC Santa Cruz platform. Survival data were obtained by PROGgene and available at . Markers for EMT and adherens junction were assessed by Western blotting and quantitative polymerase chain reaction. Effects of PKCα and FOXC2 on migration and invasion were assessed in vitro by transwell migration and invasion assays respectively. Cellular localization of E-cadherin and p120-catenin was determined by immunofluorescent staining. Promoter activity of p120-catenin was determined by dual luciferase assay using a previously validated p120-catenin reporter construct. Interaction between FOXC2 and p120-catenin promoter was verified by chromatin immunoprecipitation assay.
RESULTS: We determined that PKCα expression is necessary to maintain the migratory and invasive phenotype of both endocrine resistant and triple negative breast cancer cell lines. FOXC2 acts as a transcriptional repressor downstream of PKCα, and represses p120-catenin expression. Consequently, loss of p120-catenin leads to destabilization of E-cadherin at the adherens junction. Inhibition of either PKCα or FOXC2 is sufficient to rescue p120-catenin expression and trigger relocalization of p120-catenin and E-cadherin to the cell membrane, resulting in reduced tumor cell migration and invasion.
CONCLUSIONS: Taken together, these results suggest that breast cancer metastasis may partially be controlled through PKCα/FOXC2-dependent repression of p120-catenin and highlight the potential for PKCα signal transduction networks to be targeted for the treatment of endocrine resistant and triple negative breast cancer.

Kastenhuber ER, Lalazar G, Houlihan SL, et al.
Proc Natl Acad Sci U S A. 2017; 114(50):13076-13084 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
A segmental deletion resulting in

Bosco Schamun MB, Correa R, Graffigna P, et al.
Carney complex review: Genetic features.
Endocrinol Diabetes Nutr. 2018; 65(1):52-59 [PubMed] Related Publications
Carney complex is a multiple neoplasia syndrome having endocrine and non-endocrine manifestations. Diagnostic criteria include myxoma, lentigines, and primary pigmented nodular adrenocortical disease, amongst other signs/symptoms. In most cases it is an autosomal dominant disease, and diagnosis therefore requires study and follow-up of the family members. Inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 other disease-related genes, including PRKACA and PRKACB activating mutations, have also been related with Carney complex. This review will address the genetic aspects related to Carney complex.

Monteverde T, Tait-Mulder J, Hedley A, et al.
Calcium signalling links MYC to NUAK1.
Oncogene. 2018; 37(8):982-992 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC.

Meng L, Wang M, Du Z, et al.
Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma.
Biomed Res Int. 2017; 2017:9592501 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
LCN2 is involved in various cellular functions, including transport of small hydrophobic molecules, protection of MMP9 from proteolytic degradation, and regulating innate immunity. LCN2 is elevated in multiple human cancers, frequently being associated with tumor size, stage, and invasiveness. Our previous studies have shown that LCN2 expression could be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in esophageal squamous cell carcinoma (ESCC) by the binding of five nucleoproteins (MISP, KLF10, KLF15, PPP1R18, and RXR

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