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      Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling

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          Abstract

          Background and aims

          Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development.

          Methods

          The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2).

          Results

          PTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists.

          Conclusions

          Our findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.

          Electronic supplementary material

          The online version of this article (10.1186/s12967-017-1342-1) contains supplementary material, which is available to authorized users.

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          Most cited references29

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          Transcription factor ATF2 regulation by the JNK signal transduction pathway.

          S. Gupta, D. Campbell, B Dérijard … (1995)
          Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.
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            Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma.

            Lawrence N Kwong, James C Costello, Huiyun Liu … (2012)
            The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.
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              Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.

              Christopher Spurney, Eric Reiter, Heidi D. Nelson … (2006)
              Parathyroid hormone (PTH) regulates calcium homeostasis via the type I PTH/PTH-related peptide (PTH/PTHrP) receptor (PTH1R). The purpose of the present study was to identify the contributions of distinct signaling mechanisms to PTH-stimulated activation of the mitogen-activated protein kinases (MAPK) ERK1/2. In Human embryonic kidney 293 (HEK293) cells transiently transfected with hPTH1R, PTH stimulated a robust increase in ERK activity. The time course of ERK1/2 activation was biphasic with an early peak at 10 min and a later sustained ERK1/2 activation persisting for greater than 60 min. Pretreatment of HEK293 cells with the PKA inhibitor H89 or the PKC inhibitor GF109203X, individually or in combination reduced the early component of PTH-stimulated ERK activity. However, these inhibitors of second messenger dependent kinases had little effect on the later phase of PTH-stimulated ERK1/2 phosphorylation. This later phase of ERK1/2 activation at 30-60 min was blocked by depletion of cellular beta-arrestin 2 and beta-arrestin 1 by small interfering RNA. Furthermore, stimulation of hPTH1R with PTH analogues, [Trp1]PTHrp-(1-36) and [d-Trp12,Tyr34]PTH-(7-34), selectively activated G(s)/PKA-mediated ERK1/2 activation or G protein-independent/beta-arrestin-dependent ERK1/2 activation, respectively. It is concluded that PTH stimulates ERK1/2 through several distinct signal transduction pathways: an early G protein-dependent pathway meditated by PKA and PKC and a late pathway independent of G proteins mediated through beta-arrestins. These findings imply the existence of distinct active conformations of the hPTH1R responsible for the two pathways, which can be stimulated by unique ligands. Such ligands may have distinct and valuable therapeutic properties.
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                Author and article information

                Contributors
                Jing Tang: 465805529@qq.com
                Yan Liao: 378169367@qq.com
                Shuying He: 869180341@qq.com
                Jie Shi: 416190784@qq.com
                Liang Peng: 199255047@qq.com
                Xiaoping Xu: 673749662@qq.com
                Fang Xie: 272978167@qq.com
                Na Diao: 962218580@qq.com
                Jinlan Huang: 504575084@qq.com
                Qian Xie: 1053307805@qq.com
                Chuang Lin: 605905270@qq.com
                Xiaoying Luo: 287063849@qq.com
                Kaili Liao: 1175865120@qq.com
                Juanjuan Ma: 418367868@qq.com
                Jingyi Li: 307484423@qq.com
                Daichao Zhou: 331071165@qq.com
                Zhijun Li: 853232238@qq.com
                Jun Xu: 775650429@qq.com
                Chao Zhong: 745327707@qq.com
                Guozhen Wang: 2320052799@qq.com
                Lan Bai: +862061641539 , bailan_99@yeah.net , bailan99@hotmail.com
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 25 November 2017
                Publication date PMC-release: 25 November 2017
                Publication date Collection: 2017
                Volume: 15
                Electronic Location Identifier: 238
                Affiliations
                [1 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, , Southern Medical University, ; No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong China
                [2 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Laboratory Medicine Center, Nanfang Hospital, , Southern Medical University, ; Guangzhou, Guangdong China
                [3 ]Department of Gastroenterology, Dali Bai Autonomous Prefecture People’s Hospital, Dali, Yunnan China
                [4 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of Pathology, Nanfang Hospital, , Southern Medical University, ; Guangzhou, Guangdong China
                Article
                Publisher ID: 1342
                DOI: 10.1186/s12967-017-1342-1
                PMC ID: 5702246
                PubMed ID: 29178939
                SO-VID: d2ca6aa8-8001-4262-9da4-c1619017b7ff
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 2 May 2017
                Date accepted : 4 November 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81170354
                Funded by: National Natural Science Foundation of China (CN)
                Award ID: 81470790
                Award ID: 81500398
                Funded by: Natural Science Foundation of Guangdong Province (CN)
                Award ID: 2015A030313295
                Award ID: 2015A030310480
                Funded by: Guangzhou Pilot Project of Clinical and Translational Research Center
                Award ID: 7415696196402
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Medicine
                Keywords: parathyroid hormone-like hormone,activating transcription factor-2,proliferation,intrahepatic cholangiocarcinoma
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: parathyroid hormone-like hormone, activating transcription factor-2, proliferation, intrahepatic cholangiocarcinoma

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