• canine
• hepatocellular carcinoma
• immunohistochemistry
• pSTAT3

• Animals
• Dogs
• Dog Diseases/metabolism
• Dog Diseases/pathology
• STAT3 Transcription Factor/metabolism
• Carcinoma, Hepatocellular/veterinary
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/mortality
• Liver Neoplasms/veterinary
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/mortality
• Male
• Prognosis
• Female
• Biomarkers, Tumor/metabolism
• Immunohistochemistry/veterinary
• Gene Expression Regulation, Neoplastic

• PJ01499001 Cooperative Research Program of Center for Companion Animal Research Rural Development Administration, Korea
• Research Institute for Veterinary Science of Seoul National University

• STAT3
• apoptosis
• colorectal cancer
• histamine H1 receptor
• terfenadine

• cancer models
• molecular medicine

• Humans
• Carcinoma, Renal Cell/genetics
• Phosphorylation
• Serine/genetics
• Serine/metabolism
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism
• Kidney Neoplasms/genetics
• Cell Line, Tumor

• Consejo Nacional de Ciencia y Tecnología
• Ministerio de Ciencia e Innovación
• American Association for Cancer Research
• Red de investigación renal REDinREN

• Ovarian cancer
• Protein kinase C epsilon
• TPD52
• microRNA

• Female
• Humans
• Kruppel-Like Transcription Factors/genetics
• MicroRNAs/genetics
• Neoplasm Proteins/genetics
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Phylogeny
• Protein Kinase C-epsilon/genetics

• biomarker
• cancer treatment
• diagnosis
• poor survival
• prognosis
• protein kinase C
• therapeutic target

• JP22he0122023 Japan Agency for Medical Research and Development
• 22H03976 Japan Society for the Promotion of Science

Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.

• E2F
• GLI
• HIF-1/2
• MYT1
• NFI-A/B
• STAT3
• TBXT
• TMZ
• gliomas
• therapy
• transcription factors

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.

• Adenosine triphosphate
• Lipid metabolism
• Metabolism
• Neoplasms
• Protein processing, Post-translational
• STAT3 transcription factor

• STAT
• metastasis
• prostate cancer

• T cells
• post-translational modifications
• signaling pathway
• systemic erythematosus lupus

• STAT3
• acetylation
• methylation
• phosphorylation
• post-translational modifications

• IG 2017-19928 Associazione Italiana per la Ricerca sul Cancro
• GGP19287 Fondazione Telethon

Physalis alkekengi var. franchetii is an herb that possesses various ethnopharmacological applications. Herein, our current study focuses on the antitumor effect of a combination of physalins, which are regarded as the most representative secondary metabolites from calyces of Physalis alkekengi var. franchetii.

We mainly investigated the antitumor activity of the physalins extracted from Physalis alkekengi var. franchetii on both solid and hematologic cancers. The main cells used in this study were NCI-H1975 and U266 cells. The major assays used were the CCK-8 assay, Western blot analyses, immunofluorescence assay and Annexin V assay, and a xenograft mouse model was used.

The results showed that physalins exhibited a strong antitumoural effect on both non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells by suppressing constitutive STAT3 activity and further inhibiting the downstream target gene expression induced by STAT3 signaling, which resulted in the enhanced apoptosis of tumor cells. Moreover, physalins significantly reduced tumor growth in xenograft models of lung cancer.

Collectively, these findings demonstrated that the physalins from Physalis alkekengi var. franchetii may potentially act as cancer preventive or chemotherapeutic agents for NSCLC and MM by inhibiting the STAT3 signaling pathway. The present study served as a promising guide to further explore the precise mechanism of Physalis alkekengi var. franchetii in cancer treatment.

• Physalis
• STAT3
• apoptosis
• multiple myeloma
• non-small cell lung carcinoma

Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.

Pre conditioning injury or environmental enrichment have been shown to promote axon regeneration. Here the authors show that environmental enrichment, combined with preconditioning injury promotes regeneration via a redox signalling dependent mechanism.

• STAT3
• cancer therapy
• drug resistance
• feedback regulation
• mutant p53 (mtp53)
• wild-type p53 (wtp53)

• Cancer
• Drug resistance
• EMT
• Immune evasion
• Metastasis
• Protein kinase C
• Tumor promotion

• 5-FU resistance
• JAK/STAT3 pathway
• NHE1
• gastric cancer

• Science and Technology Program for Public Wellbeing of Qingdao

• CXCR1
• CXCR2
• CXCR3
• Chemokine receptors
• Migration
• Morphology
• Protein kinase C

• PPAR
• genome-wide association study
• pancreatic cancer susceptibility
• pathway analysis
• single-nucleotide polymorphism

• Aged
• Biomarkers, Tumor/genetics
• Case-Control Studies
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Mediator Complex Subunit 1/genetics
• Middle Aged
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Peroxisome Proliferator-Activated Receptors/genetics
• Polymorphism, Single Nucleotide
• Prognosis
• Protein Kinase C beta/genetics
• Protein Kinase C-alpha/genetics
• Quantitative Trait Loci
• Survival Rate

• HHSN268201100011I NHLBI NIH HHS
• HHSN268201100011C NHLBI NIH HHS
• R01 CA154823 NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• Howard Hughes Medical Institute
• HHSN261200800001C NCI NIH HHS
• P30 CA014236 NCI NIH HHS
• K07 CA140790 NCI NIH HHS

• alternative splicing
• cancer
• cell death
• cell differentiation
• cell proliferation
• transcription factors

• Alternative Splicing/genetics
• Cell Lineage/genetics
• DNA/metabolism
• Humans
• Models, Biological
• Neoplasms/genetics
• Neoplasms/pathology
• Transcription Factors/metabolism

• Cytokine and growth factor receptor signaling
• Gliomas
• Protein tyrosine kinases
• STAT proteins
• Transcription regulation

• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Cell Transformation, Neoplastic
• Glioma/metabolism
• Glioma/pathology
• Humans
• Janus Kinases/metabolism
• Phosphorylation
• STAT Transcription Factors/metabolism
• Signal Transduction

Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.

• STAT3
• gene transcription and targeted therapy
• lymphoma
• oncogene

The 57 kDa antigen recognized by the Ki-1 antibody, is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7% identity and 67.4% similarity with serpin mRNA binding protein 1, which is also named CGI-55, or plasminogen activator inhibitor type-1-RNA binding protein-1, indicating that they might be paralog proteins, possibly with similar or redundant functions in human cells. Through the identification of their protein interactomes, both regulatory proteins have been functionally implicated in transcriptional regulation, mRNA metabolism, specifically RNA splicing, the regulation of mRNA stability, especially, in the context of the progesterone hormone response, and the DNA damage response. Both proteins also show a complex pattern of post-translational modifications, involving Ser/Thr phosphorylation, mainly through protein kinase C, arginine methylation and SUMOylation, suggesting that their functions and locations are highly regulated. Furthermore, they show a highly dynamic cellular localization pattern with localizations in both the cytoplasm and nucleus as well as punctuated localizations in both granular cytoplasmic protein bodies, upon stress, and nuclear splicing speckles. Several reports in the literature show altered expressions of both regulatory proteins in a series of cancers as well as mutations in their genes that may contribute to tumorigenesis. This review highlights important aspects of the structure, interactome, post-translational modifications, sub-cellular localization and function of both regulatory proteins and further discusses their possible functions and their potential as tumor markers in different cancer settings.

• Cancer
• Cell signaling
• Regulatory protein
• Protein interactions
• Post-translational modifications

Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specific modulators acting via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic efforts had recently led to the identification of AJH-836, a DAG-lactone with preferential affinity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9, and MMP10 were among the genes most prominently induced by PMA, an effect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics efforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of differentially regulating PKC isozyme-specific function in cellular models.

• GRIM-19
• STAT3/HIF-1α signaling
• colorectal cancer
• epithelial-mesenchymal transition
• invasion

• 4EBP-1
• Apoptosis
• Napabucasin
• Osteosarcoma
• Protein synthesis
• eIF4E

• PKCε
• cross talk
• insulin resistance
• phosphoproteomics
• systems biology

• MPG
• CTRP8
• DNA damage repair
• RXFP1
• alkylating drug
• base excision repair
• temozolomide

• Adiponectin/metabolism
• Antineoplastic Agents, Alkylating/therapeutic use
• Apoptosis/drug effects
• Brain Neoplasms/drug therapy
• Caspase 3/metabolism
• Caspase 7/metabolism
• Cell Line, Tumor
• DNA Breaks, Double-Stranded/drug effects
• DNA Glycosylases/genetics
• DNA Glycosylases/metabolism
• DNA Repair
• Drug Resistance, Neoplasm
• Glioblastoma/drug therapy
• Humans
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Receptors, G-Protein-Coupled/metabolism
• Receptors, Peptide/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/drug effects
• Temozolomide/therapeutic use
• bcl-X Protein/metabolism

• CyclinD1
• Gefitinib
• PKM2
• STAT3
• Shikonin

• A549 Cells
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents, Phytogenic/pharmacology
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carrier Proteins/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Cyclin D1/drug effects
• Drug Synergism
• ErbB Receptors/drug effects
• Gefitinib
• Humans
• Immunohistochemistry
• Lung Neoplasms/drug therapy
• Membrane Proteins/drug effects
• Mice
• Mice, Nude
• Naphthoquinones/pharmacology
• Quinazolines/pharmacology
• STAT3 Transcription Factor/drug effects
• Signal Transduction/drug effects
• Sincalide/drug effects
• Thyroid Hormones
• Thyroid Hormone-Binding Proteins

Several efforts have been focused on identification of pathways involved in malignancy, progression, and response to treatment in Glioblastoma (GB). Overexpression of PKCε was detected in histological samples from GB, anaplastic astrocytoma, and gliosarcoma and is considered an important marker of negative disease outcome. In multiple studies on GB, autophagy has been shown as a survival mechanism during cellular stress, contributing to resistance against anti-cancer agents. The main object of this research was to determine the influence of PKCε downregulation on the expression of genes involved in autophagy pathways in glioblastoma cell lines U-138 MG and U-118 MG with high PKCε level.

We conducted siRNA-mediated knockdown of PKCε in glioblastoma cell lines and studied the effects of autophagy pathway. The expression of autophagy-related genes was analyzed using qPCR and Western blot analysis was carried out to assess protein levels. Immunostaining was used to detect functional autophagic maturation process.

We found that these cell lines exhibited a high basal expression of autophagy-related genes. Our results suggest that the loss of PKCε contributes to the downregulation of genes involved in autophagy pathways. Moreover, most of the changes we observed in Western blot analysis and endogenous immunofluorescence experiments confirmed dysfunction of autophagy programs. We found that knockdown of PKCε induced a decrease in the expression of Beclin1, Atg5, PI3K, whereas the expression of other autophagy-related proteins mTOR and Bcl2 was increased. Treatment of control siRNA glioma cells with rapamycin-induced autophagosome formation and increase in LC3-II level and caused a decrease in the expression of p62. Additionally, PKCε siRNA caused a diminution in the Akt phosphorylation at Ser473 and in the protein level in both cell lines. Moreover, we observed reduction in the adhesion of glioblastoma cells, accompanied by the decrease in total FAK protein level and phosphorylation.

Effects of down-regulation of PKCε in glioma cells raised the possibility that the expression of PKCε is essential for the autophagic signal transduction pathways in these cells.

Thus, our results identify an important role of PKCε in autophagy and may, more importantly, identifyit as a novel therapeutic target.

• Autophagy
• Gliomas
• Protein kinase C epsilon

• Animals
• Antineoplastic Agents, Phytogenic/pharmacokinetics
• Antineoplastic Agents, Phytogenic/therapeutic use
• Benzoquinones/chemistry
• Benzoquinones/pharmacokinetics
• Benzoquinones/therapeutic use
• Blood-Brain Barrier/metabolism
• Blood-Brain Barrier/pathology
• Brain Neoplasms/drug therapy
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Glioblastoma/drug therapy
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Humans
• Nigella sativa/chemistry

• Antimetastasis
• Antiproliferative activity
• Histone deacetylase inhibitors
• Synthesis
• β-Carbolines

Angiogenesis is the development of new blood vessels, which is required for tumor growth and metastasis. Signal transducer and activator of transcription factor 3 (STAT3) is a transcription factor that regulates a variety of cellular events including proliferation, differentiation and apoptosis. Previous studies revealed that activation of STAT3 promotes tumor angiogenesis. In this review, we described the activities of STAT3 signaling in different cell types involved in angiogenesis. Particularly, we elucidated the molecular mechanisms of STAT3-mediated gene regulation in angiogenic endothelial cells in response to external stimulations such as hypoxia and inflammation. The potential for STAT3 as a therapeutic target was also discussed. Overall, this review provides mechanistic insights for the roles of STAT3 signaling in tumor angiogenesis.

• STAT3
• endothelial cells
• transcriptional regulation
• tumor angiogenesis

• Chemo-Resistance
• Colon Cancer
• Signal Transduction
• Tumor Progression

• Raf kinase inhibitor protein
• metastasis
• non-small cell lung cancer
• signal transducer and activator of transcription 3

CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.

• CD147
• dimerization
• hepatocellular carcinoma cells
• metastasis
• small molecule inhibitor

• Apigenin-7-O-β-D-(-6″-p-coumaroyl)-glucopyranoside
• Hemeoxygenase 1
• Mitochondrial oxidative stress
• Nuclear factor erythroid 2 p45 related factor 2
• Protein kinase Cε

Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state.

• Glioma
• STAT3
• Serine 727
• Tyrosine 705

• liver cancer
• interleukin-6
• stat3
• tumor suppression
• tumor microenvironment

The role of Snail and serpin peptidase inhibitor clade A member 1 (serpinA1) in tumorigenesis has been previously identified. However, the exact role and mechanism of these proteins in progression of colorectal cancer (CRC) are controversial. In this study, we investigated the role of Snail and serpinA1 in colorectal cancer (CRC) and examined the mechanisms through which these proteins mediate CRC progression. Immunohistochemical analysis of 528 samples from patients with CRC showed that elevated expression of Snail or serpinA1 was correlated with advanced stage, lymph node metastasis, and poor prognosis. Moreover, we detected a correlation between Snail and serpinA1 expression. Functional studies performed using the CRC cell lines DLD-1 and SW-480 showed that overexpression of Snail or serpinA1 significantly increased CRC cell invasion and migration. Conversely, knockdown of Snail or serpinA1 expression suppressed CRC cell invasion and migration. ChIP analysis revealed that Snail regulated serpinA1 by binding to its promoter. In addition, fibronectin mediated Snail and serpinA1 signaling was involved in CRC cell invasion and migration. Taken together, our data showed that Snail and serpinA1 promoted CRC progression through fibronectin. These findings suggested that Snail and serpinA1 were novel prognostic biomarkers and candidate therapeutic targets in CRC.

• Snail
• colorectal cancer
• fibronectin
• prognosis
• serpinA1

PKCε is a transforming oncogene and a predictive biomarker of various human cancers. However, a precise in vivo link of PKCε to cancer induction, progression and metastasis remain undefined. To achieve these goals, we generated tissue specific conditional PKCε knockout mice (PKCε-CKO) using cre-lox technology. Homozygous PKCε^LoxP/LoxP mice have normal body weight and phenotype. To determine what effect loss of PKCε would have on the prostate, the PKCε^LoxP/LoxP mice were bred to probasin cre (PB-Cre4⁺) mice which express cre specifically in the prostate epithelium of postnatal mice. Western blot and immunohistochemical analyses showed reduced levels of PKCε specifically in the prostate of PKCε-CKO mice. Histopathological analyses of prostate from both PKCε^LoxP/LoxP and prostate PKCε-CKO mice showed normal pathology. To determine the functional impact of prostate specific deletion of PKCε on prostate tumor growth, we performed an orthotopic xenograft study. Transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMPC1, 2×10⁶) were implanted in the prostate of PKCε-CKO mice. Mice were sacrificed at 6th week post-implantation. Results demonstrated a significant (P<0.05) decrease in the growth of TRAMPC1 cells-derived xenograft tumors in PKCε-CKO mice compared to wild type. To determine a link of PKCε to ultraviolet radiation (UVR) exposure-induced epidermal Stat3 phosphorylation, PKCε^LoxP/LoxP mice were bred to tamoxifen-inducible K14 Cre mice. PKCε deletion in the epidermis resulted in inhibition of UVR-induced Stat3 phosphorylation. In summary, our novel PKCε^LoxP/LoxP mice will be useful for defining the link of PKCε to various cancers in specific organ, tissue, or cells.

• PKCεLoxP/LoxP mice
• transgenic mice

• ErbB receptor subtypes
• OSCC cells
• PKCɛ
• cancer-associated fibroblasts
• p95HER2