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// Chi Yan 1, 2 , Yang Lei 1, 2 , Tong-Jun Lin 2, 3, 5 , David W. Hoskin 2, 4 , Averil Ma 6 and Jun Wang 1, 2, 3, 5 1 Canadian Center for Vaccinology, Halifax, Nova Scotia, Canada 2 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 3 Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 4 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada 5 IWK Health Centre, Halifax, Nova Scotia, Canada 6 Department of Medicine, University of California, San Francisco, California, USA Correspondence to: Jun Wang, email: jun.wang@dal.ca Keywords: IL-17 receptor C, A20, JNK1, JNK2, B16 melanoma Received: February 04, 2017 Accepted: April 17, 2017 Published: May 11, 2017 ABSTRACT The IL-17/IL-17R axis has controversial roles in cancer, which may be explained by tumor-specific results. Here, we describe a novel molecular mechanism underlying IL-17RC-controlled tumor-specific proliferation. Triggered by IL-17RC knockdown (KD), B16 melanoma and 4T1 carcinoma cells inversely altered homeostatic tumor proliferation and tumor growth in vitro and in vivo . In contrast to the existing dogma that IL-17RC-dependent signaling activates the JNK pathway, IL-17RC KD in both tumor cell lines caused aberrant expression and activation of different JNK isoforms along with markedly diminished levels of the ubiquitin-editing enzyme A20. We demonstrated that differential up-regulation of JNK1 and JNK2 in the two tumor cell lines was responsible for the reciprocal regulation of c-Jun activity and tumor-specific proliferation. Furthermore, we showed that A20 reconstitution of IL-17RCKD clones with expression of full-length A20, but not a truncation-mutant, reversed aberrant JNK1/JNK2 activities and tumor-specific proliferation. Collectively, our study reveals a critical role of IL-17RC in maintaining baseline A20 production and a novel role of the IL-17RC-A20 axis in controlling JNK isoform-dependent tumor-specific homeostatic proliferation.

// Sike Hu 1 , Xiaoli Dong 1 , Wenjuan Gao 1 , Dwayne Stupack 2 , Yanhua Liu 1, 3 , Rong Xiang 1, 3, 4 and Na Li 1, 3, 4 1 School of Medicine, Nankai University, Tianjin 300071, China 2 Department of Reproductive Medicine, Division of Gynecologic Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0987, United States 3 Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, Tianjin 300071, China 4 Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin 300071, China Correspondence to: Na Li, email: lina08@nankai.edu.cn Rong Xiang, email: rxiang@nankai.edu.cn Keywords: JNK2, p-JNK2, Fra1, EMT Received: December 21, 2016 Accepted: March 30, 2017 Published: April 28, 2017 ABSTRACT Fos-related antigen 1 (Fra1) has been proposed as a gatekeeper of the mesenchymal-epithelial transition to epithelial-mesenchymal transition. Here, we showed that de-phosphorylated JNK2 increased the expression of Fra1 by promoting the expression of c-Jun and Jun-B. Conversely, phosphorylated JNK2 suppressed its expression via enhancing the ubiquitination of c-Jun and Jun-B. These data provided insights into the regulatory mechanism of JNK2 on the expression of Fra1. Our study thus demonstrated that the conversion of JNK2 from its phosphorylation to de-phosphorylation status promoted the switch of breast cancer cells from mesenchymal-epithelial transition to epithelial-mesenchymal transition.

Bladder cancer is one of the most common malignancies of the urinary system, and the 5-year survival rate remains low. A comprehensive understanding of the carcinogenesis and progression of bladder cancer is urgently needed to advance treatment. c-Jun N-terminal kinase-2 (JNK2) exhibits both tumor promoter and tumor suppressor actions, depending on tumor type. Here, we analyzed the JNK2 function in bladder cancer. Using gene expression microarrays, we demonstrated that JNK2 mRNA is downregulated in an orthotopic rat model of bladder cancer. JNK2 protein levels were lower in rat and human bladder cancer tissues than in normal tissues, and the levels correlated with those of p53. Moreover, JNK2 phosphorylated p53 at Thr-81, thus protecting p53 from MDM2-induced proteasome degradation. Decreased expression of JNK2 in T24 cells conferred resistance to cell death induced by mitomycin C. Furthermore, lower JNK2 expression was associated with poorer overall survival among patients who underwent radical cystectomy. These results indicate that JNK2 acts as a tumor suppressor in bladder cancer, and that decreased JNK2 expression promotes bladder cancer tumorigenesis.

Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation.

// Michael A. Cantrell 1, * , Nancy D. Ebelt 1, * , Adam D. Pfefferle 3, 4 , Charles M. Perou 3, 4, 5 , Carla Lynn Van Den Berg 1, 2 1 Institute of Cellular & Molecular Biology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA 2 Division of Pharmacology &Toxicology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA 3 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA 5 Department of Genetics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA * These authors have contributed equally to this work Correspondence to: Carla Lynn Van Den Berg, e-mail: carla.vandenberg@austin.utexas.edu Keywords: breast cancer, JNK2, p53, Notch1, BRCA1 Received: March 13, 2015 Accepted: April 13, 2015 Published: April 25, 2015 ABSTRACT Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.