Expression of Protein Kinase C Family in Human Hepatocellular Carcinoma

Lu, Hsiu-Chin; Chou, Fen‐Pi; Yeh, Kun‐Tu; Chang, Ya‐Sian; Hsu, Nancy; Chang, Jan‐Gowth

doi:10.1007/s12253-009-9228-z

Cited by 11 publications

(11 citation statements)

References 56 publications

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“…Accordingly, Ang II can activate AT1, which in turn activates PKC signaling. PKC is a serine/threonine kinase that plays a key role in several steps of the signal transduction pathway, including cell proliferation, migration, and invasion of HCC [47,48]. It has also been demonstrated that inhibition of PKC activity reduces motility and invasion properties of HCC cells [49].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Ji¹,

Wang²,

Li³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The pathogenesis of hepatocellular carcinoma (HCC) is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation. Angiotensin II (Ang II) behaves as an endogenous pro-inflammatory molecule playing a significant role in HCC, however, the molecular link between Ang II, proliferation and inflammation remains unclear. Methods: Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with Ang II at the indicated concentrations for 24, 48, 72 h. MTT, BrdU ELISA, plate colony formation assay, immunohistochemistry, ELISA, small-interfering RNA(siRNA) transfection, quantitative real-time PCR and western blot were applied to assess their functional, morphological and molecular mechanisms in HCC cell lines. Results: High expression of Ang II type 1 receptor (AT1) and low expression of AT2 in HCC cells and tissues were found. Next, Ang II could significantly enhance cell growth and proliferation. Albeit Ang II slightly increased the percentage of HCC cells in the G0/G1 phase using flow cytometry analysis, no statistically significant alterations were shown. Further studies suggested that Ang II could directly induce proliferation associated proteins C-myc and proliferating cell nuclear antigen (PCNA) expressions, and inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) productions in HCC cells. Interestingly, blocking AT1 and AT1 siRNA evidently inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cells. More importantly, these effects may be mediated by AT1/PKC/NF-κB signaling pathway in HCC cell lines. Conclusions: The results propose that Ang II/AT1/PKC/NF-κB signaling pathway is necessary for proliferation and inflammation of HCC cells, which increases our understanding of the pathogenesis and provides clues for developing new strategies against Ang II-related progress of HCC.

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Section: Discussionmentioning

confidence: 99%

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Ji¹,

Wang²,

Li³

et al. 2016

Cell Physiol Biochem

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“…The activities of six members of the AGC family, ten members of the TK family, five members of the STE family, two members of the CMGC family and PDK2 were associated with elevated activity in HCC (See supplemental Table S5); as expected, these kinases demonstrating elevated activity included PKCs, ROCK2, and MAPKs confirming the Motif-X findings indicating that basophilic-motifs were overrepresented. Among those kinases demonstrating elevated activities, one member of the PKCs (PKC), as well as five members of the TK family (ITK, Lyn, BLK, BRK, and SRM) and PDK2 have not yet been functionally described in HCC, whereas PKC␦ and PKC␤ were previously reported downregulated in HCC (56).…”

Section: Phosphoproteome Profiles Of Hcc Tumor and Wild Typementioning

confidence: 99%

In Vivo Phosphoproteome Analysis Reveals Kinome Reprogramming in Hepatocellular Carcinoma

Lang

Wang³

et al. 2018

Molecular & Cellular Proteomics

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Aberrant kinases contribute to cancer survival and proliferation. Here, we quantitatively characterized phosphoproteomic changes in an HBx-transgenic mouse model of hepatocellular carcinoma (HCC) using high-resolution mass spectrometry, profiled 22,539 phosphorylation sites on 5431 proteins. Using a strategy to interpret kinase- substrate relations in HCC and to uncover predominant kinases in tumors, our results, revealed elevated kinase activities of Src family kinases (SFKs), PKCs, MAPKs, and ROCK2 in HCC, representatives of which were further validated in cell models and clinical HBV-positive HCC samples. Inhibitor combinations targeting Src and PKCs or ROCK2 both synergized significantly to inhibit cell growth. In addition, we demonstrated that phosphorylation at Src Ser17 directly affects its kinase activity. Our phosphoproteome data facilitated the construction of a detailed molecular landscape in HCC and should serve as a resource for the cancer community. Our strategy is generally applicable to targeted therapeutics, also highlights potential mechanisms of kinase regulation.

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“…PKCε levels are elevated in prostate cancer relative to benign prostatic epithelia [161], and a correlation with aggressiveness of human prostate cancer has been found [4]. PKCη, an isoform related to PKCε, has also been shown to be up-regulated in some cancers [162–163] but down-regulated in others [164]. …”

Section: Pkcε: An Oncogenic and Metastatic Kinasementioning

confidence: 99%

Protein kinase C and cancer: what we know and what we do not

et al. 2013

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Since their discovery in the late 1970’s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.

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Expression of Protein Kinase C Family in Human Hepatocellular Carcinoma

Cited by 11 publications

References 56 publications

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

In Vivo Phosphoproteome Analysis Reveals Kinome Reprogramming in Hepatocellular Carcinoma

Protein kinase C and cancer: what we know and what we do not

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