Top

Journal of Translational Medicine

Published in:

Open Access 01-12-2017 | Research

IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling

Authors: Cheng Chen, Xuejun Zhang

Published in: Journal of Translational Medicine | Issue 1/2017

Abstract

Background

The IRE1α-XBP1 pathway is the most conserved branch of the unfolded protein response pathways, which are activated during endoplasmic reticulum (ER) stress caused by the accumulation of unfolded/misfolded proteins in the ER lumen. The IRE1α-XBP1 pathway plays a critical role in various cancers. However, the role of this pathway in melanoma cell growth remains unclear.

Methods

Sixty-one pairs of melanoma specimens and corresponding normal tissues from patients were stained with XBP1. Then, XBP1 splicing levels were detected in human tissues and cell lines at the mRNA level. IL-6 expression levels were determined in both melanocytes (HEMn-MP) and melanoma cells (Mel-RMu) overexpressing the spliced form of XBP1 (XBP1s). IL-6 expression was also examined in 4μ8C-treated HEMn-MP and Mel-RMu cells overexpressing IRE1α. Next, we analyzed potential XBP1s binding sites within the IL-6 promoter and conducted ChIP experiments. IL-6/STAT3 signaling was detected by western blotting. Melanoma cell proliferation was examined by CCK8 and BrdU assays.

Results

The mRNA and protein expression levels of XBP1s were significantly elevated in human melanoma tissues and cell lines compared with normal tissues or melanocytes, thus indicating the activation of the IRE1α-XBP1 branch in melanoma. Ectopic expression of IRE1α or XBP1s robustly enhanced IL-6 expression in HEMn-MP and Mel-RMu cells. Moreover, the inhibition of the RNase activity of IRE1α also abolished the effect of IRE1α in promoting IL-6 expression. Mechanistically, XBP1 binds the IL-6 promoter and activates its expression. Furthermore, secreted IL-6 functions in an autocrine/paracrine manner, activates the intracellular JAK/STAT3 pathway and promotes the proliferation of melanoma cells.

Conclusion

Our results reveal that the IRE1α-XBP1 pathway regulates Mel-RMu cell proliferation and progression by activating IL-6/STAT3 signaling.

Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene. 2003;22:3138–51.CrossRefPubMed

Hersey P, Zhuang L, Zhang XD. Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. Int Rev Cytol. 2006;251:131–58.CrossRefPubMed

Sykes EK, Mactier S, Christopherson RI. Melanoma and the unfolded protein response. Cancers. 2016;8:30.CrossRefPubMedCentral

Croft A, Tay KH, Boyd SC, Guo ST, Jiang CC, Lai F, Tseng HY, Jin L, Rizos H, Hersey P, Zhang XD. Oncogenic activation of MEK/ERK primes melanoma cells for adaptation to endoplasmic reticulum stress. J Invest Dermatol. 2014;134:488–97.CrossRefPubMed

Corazzari M, Rapino F, Ciccosanti F, Giglio P, Antonioli M, Conti B, Fimia GM, Lovat PE, Piacentini M. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma. Cell Death Differ. 2015;22:946–58.CrossRefPubMed

Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014;124:1406–17.CrossRefPubMedPubMedCentral

Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29.CrossRefPubMed

Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005;74:739–89.CrossRefPubMed

Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6.CrossRefPubMed

10.

Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–91.CrossRefPubMed

11.

Hersey P, Zhang XD. Adaptation to ER stress as a driver of malignancy and resistance to therapy in human melanoma. Pigment Cell Melanoma Res. 2008;21:358–67.CrossRefPubMed

12.

Zhuang L, Scolyer RA, Lee CS, McCarthy SW, Cooper WA, Zhang XD, Thompson JF, Hersey P. Expression of glucose-regulated stress protein GRP78 is related to progression of melanoma. Histopathology. 2009;54:462–70.CrossRefPubMed

13.

Jiang CC, Yang F, Thorne RF, Zhu BK, Hersey P, Zhang XD. Human melanoma cells under endoplasmic reticulum stress acquire resistance to microtubule-targeting drugs through XBP-1-mediated activation of Akt. Neoplasia. 2009;11:436–47.CrossRefPubMedPubMedCentral

14.

Denoyelle C, Abou-Rjaily G, Bezrookove V, Verhaegen M, Johnson TM, Fullen DR, Pointer JN, Gruber SB, Su LD, Nikiforov MA, et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat Cell Biol. 2006;8:1053–63.CrossRefPubMed

15.

Ding BB, Yu JJ, Yu RY, Mendez LM, Shaknovich R, Zhang Y, Cattoretti G, Ye BH. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood. 2008;111:1515–23.CrossRefPubMedPubMedCentral

16.

Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R, Yu H. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 2002;21:7001–10.CrossRefPubMed

17.

Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, Lin J. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011;71:7226–37.CrossRefPubMedPubMedCentral

18.

Shao M, Shan B, Liu Y, Deng Y, Yan C, Wu Y, Mao T, Qiu Y, Zhou Y, Jiang S, et al. Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARα axis signalling. Nat Commun. 2014;5:3528.PubMed

19.

Yang C, Xu Z, Zhao Z, Li L, Zhao T, Peng D, Xu M, Rong R, Long YQ, Zhu T. A novel proteolysis-resistant cyclic helix B peptide ameliorates kidney ischemia reperfusion injury. Biochim Biophys Acta. 2014;1842:2306–17.CrossRefPubMed

20.

Li QL, Gu FM, Wang Z, Jiang JH, Yao LQ, Tan CJ, Huang XY, Ke AW, Dai Z, Fan J, Zhou J. Activation of PI3K/AKT and MAPK pathway through a PDGFRbeta-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma. PLoS ONE. 2012;7:e33379.CrossRefPubMedPubMedCentral

21.

Yang C, Liu J, Li L, Hu M, Long Y, Liu X, Zhu T, Huang X, Zhao S, Liu S, Rong R. Proteome analysis of renoprotection mediated by a novel cyclic helix B peptide in acute kidney injury. Sci Rep. 2015;5:18045.CrossRefPubMedPubMedCentral

22.

Yang C, Zhao T, Zhao Z, Jia Y, Li L, Zhang Y, Song M, Rong R, Xu M, Nicholson ML, et al. Serum-stabilized naked caspase-3 siRNA protects autotransplant kidneys in a porcine model. Mol Ther. 2014;22:1817–28.CrossRefPubMedPubMedCentral

23.

Kanemoto S, Kondo S, Ogata M, Murakami T, Urano F, Imaizumi K. XBP1 activates the transcription of its target genes via an ACGT core sequence under ER stress. Biochem Biophys Res Commun. 2005;331:1146–53.CrossRefPubMed

24.

Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318:944–9.CrossRefPubMedPubMedCentral

25.

Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN, Davidson NO, Kaufman RJ. IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab. 2012;16:473–86.CrossRefPubMedPubMedCentral

26.

Deng Y, Wang ZV, Tao C, Gao N, Holland WL, Ferdous A, Repa JJ, Liang G, Ye J, Lehrman MA, et al. The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism. J Clin Invest. 2013;123:455–68.CrossRefPubMed

27.

Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med. 2011;17:356–65.CrossRefPubMedPubMedCentral

28.

Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411–8.CrossRefPubMedPubMedCentral

29.

Toosi S, Orlow SJ, Manga P. Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8. J Invest Dermatol. 2012;132:2601–9.CrossRefPubMedPubMedCentral

30.

Hoejberg L, Bastholt L, Schmidt H. Interleukin-6 and melanoma. Melanoma Res. 2012;22:327–33.CrossRefPubMed

31.

Hoejberg L, Bastholt L, Johansen JS, Christensen IJ, Gehl J, Schmidt H. Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma. Melanoma Res. 2012;22:287–93.CrossRefPubMed

32.

Liu Y, Shao M, Wu Y, Yan C, Jiang S, Liu J, Dai J, Yang L, Li J, Jia W, et al. Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses. J Hepatol. 2015;62:590–8.CrossRefPubMed

33.

Xu T, Yang L, Yan C, Wang X, Huang P, Zhao F, Zhao L, Zhang M, Jia W, Liu Y. The IRE1alpha-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic beta-cells. Cell Res. 2014;24:1137–40.CrossRefPubMedPubMedCentral

34.

Thorpe JA, Schwarze SR. IRE1alpha controls cyclin A1 expression and promotes cell proliferation through XBP-1. Cell Stress Chaperones. 2010;15:497–508.CrossRefPubMed

35.

Darnell JE. Validating Stat3 in cancer therapy. Nat Med. 2005;11:595–6.CrossRefPubMed

36.

Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11:1314–21.CrossRefPubMed

37.

Kortylewski M, Jove R, Yu H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev. 2005;24:315–27.CrossRefPubMed

38.

Cao HH, Chu JH, Kwan HY, Su T, Yu H, Cheng CY, Fu XQ, Guo H, Li T, Tse AK, et al. Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma. Sci Rep. 2016;6:21731.CrossRefPubMedPubMedCentral

Title: IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling
Authors: Cheng Chen
Xuejun Zhang
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-017-1147-2

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2017

Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy

Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection

CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest

Altered Semmes–Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects

Analysis of necroptotic proteins in failing human hearts

Urinary collagen degradation products as early markers of progressive renal fibrosis

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page