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CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma

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Tumor Biology

Abstract

Chemokine ligand 18 (CCL18) has been associated with hepatocellular carcinoma (HCC) metastasis. Here, we demonstrated a novel mechanism through which CCL18 enhances cell migration, invasion, and epithelial–mesenchymal transition (EMT) in HCC. (1) Using immunohistochemistry, we analyzed the expression of PITPNM3, a molecule that correlated with CCL18 signaling, in 149 HCC tissue specimens. The results showed that PITPNM3 expression is highly associated with tumor metastasis and differentiation; (2) in vitro experiments showed that CCL18 enhances cell migration, invasion, and EMT in PITPNM3(+) HCC cells but not in PITPNM3(-) cells. Silencing of PITPNM3 by short interfering RNA (siRNA) inhibited the induction of cell migration, invasion, and EMT by CCL18; (3) Cell migration, invasion, and EMT induced by CCL18 accompanied with the phosphorylation of IKK and IKBα as well as p65 nuclear translocation in PITPNM3(+) HCC cells, but not in the cells that PITPNM3 is silenced with siRNA, implying that the activation of NF-κB signaling is involved in the action of CCL18/PITPNM3. These results suggest that CCL18 enhances HCC cell migration, invasion, and EMT through the expression of PITPNM3 and the activation of the NF-κB signaling pathway.

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Abbreviations

HCC:

Hepatocellular carcinoma

CCL18:

Chemokine ligand 18

EMT:

Epithelial mesenchymal transition

TAM:

Tumor-associated macrophages

IHC:

Immunohistochemistry

NF-κB:

Nuclear factor kappa B

IKB:

Inhibitor of NF-κB

IKK:

IκB kinase

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  3. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7:448–58.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  5. Bridges JF, Joy SM, Gallego G, Kudo M, Ye SL, Han KH, et al. Needs for hepatocellular carcinoma control policy in the Asia-Pacific region. Asian Pac J Cancer Prev. 2011;12:2585–91.

    PubMed  Google Scholar 

  6. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.

    Article  CAS  PubMed  Google Scholar 

  7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou SL, Zhou ZJ, Hu ZQ, Li X, Huang XW, Wang Z, et al. Cxcr2/cxcl5 axis contributes to epithelial-mesenchymal transition of hcc cells through activating pi3k/akt/gsk-3beta/Snail signaling. Cancer Lett. 2015;358:124–35.

    Article  CAS  PubMed  Google Scholar 

  9. Gao Y, Ruan B, Liu W, Wang J, Yang X, Zhang Z, et al. Knockdown of cd44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial–mesenchymal transition. Oncotarget. 2015.

  10. Li L, Li W. Epithelial–mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation. Pharmacol Ther. 2015.

  11. Song R, Song H, Liang Y, Yin D, Zhang H, Zheng T, et al. Reciprocal activation between atpase inhibitory factor 1 and nf-kappab drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology. 2014;60:1659–73.

    Article  CAS  PubMed  Google Scholar 

  12. Huang RY, Guilford P, Thiery JP. Early events in cell adhesion and polarity during epithelial–mesenchymal transition. J Cell Sci. 2012;125:4417–22.

    Article  CAS  PubMed  Google Scholar 

  13. Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21:35–43.

    Article  CAS  PubMed  Google Scholar 

  14. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144:512–27.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a tgf-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goetz JG, Minguet S, Navarro-Lerida I, Lazcano JJ, Samaniego R, Calvo E, et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011;146:148–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luker KE, Lewin SA, Mihalko LA, Schmidt BT, Winkler JS, Coggins NL, et al. Scavenging of cxcl12 by cxcr7 promotes tumor growth and metastasis of cxcr4-positive breast cancer cells. Oncogene. 2012;31:4750–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Roussos ET, Condeelis JS, Patsialou A. Chemotaxis in cancer. Nat Rev Cancer. 2011;11:573–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010;16:133–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen J, Yao Y, Gong C, Yu F, Su S, Liu B, et al. Ccl18 from tumor-associated macrophages promotes breast cancer metastasis via pitpnm3. Cancer Cell. 2011;19:541–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Su S, Liu Q, Chen J, Chen F, He C, Huang D, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25:605–20.

    Article  CAS  PubMed  Google Scholar 

  22. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, et al. Tumor-associated macrophages produce interleukin 6 and signal via stat3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 2014;147:1393–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.

    Article  CAS  PubMed  Google Scholar 

  24. Heindryckx F, Gerwins P. Targeting the tumor stroma in hepatocellular carcinoma. World J Hepatol. 2015;7:165–76.

    Article  PubMed  PubMed Central  Google Scholar 

  25. He C, Su S, Chen F, Huang D, Zheng F, Huang W, et al. Overexpression of pitpnm3 promotes hepatocellular carcinoma cell metastasis. Chin Sci Bull. 2014;59:1326–33.

    Article  CAS  Google Scholar 

  26. Theiss AL. Sphingosine-1-phosphate: driver of nfkappab and stat3 persistent activation in chronic intestinal inflammation and colitis-associated cancer. JAKSTAT. 2013;2, e24150.

    PubMed  PubMed Central  Google Scholar 

  27. Pal S, Bhattacharjee A, Ali A, Mandal NC, Mandal SC, Pal M. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa b and p53 mutual antagonism. J Inflamm (Lond). 2014;11:23.

    Article  CAS  Google Scholar 

  28. Karin M, Greten FR. Nf-κb: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–59.

    Article  CAS  PubMed  Google Scholar 

  29. Ghosh S, Hayden MS. Celebrating 25 years of nf-kappab research. Immunol Rev. 2012;246:5–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    Article  CAS  PubMed  Google Scholar 

  31. Prasse A, Pechkovsky DV, Toews GB, Schafer M, Eggeling S, Ludwig C, et al. Ccl18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56:1685–93.

    Article  CAS  PubMed  Google Scholar 

  32. Pochetuhen K, Luzina IG, Lockatell V, Choi J, Todd NW, Atamas SP. Complex regulation of pulmonary inflammation and fibrosis by ccl18. Am J Pathol. 2007;171:428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chang CY, Lee YH, Leu SJ, Wang CY, Wei CP, Hung KS, et al. Cc-chemokine ligand 18/pulmonary activation-regulated chemokine expression in the cns with special reference to traumatic brain injuries and neoplastic disorders. Neuroscience. 2010;165:1233–43.

    Article  CAS  PubMed  Google Scholar 

  34. Islam SA, Ling MF, Leung J, Shreffler WG, Luster AD. Identification of human ccr8 as a ccl18 receptor. J Exp Med. 2013;210:1889–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Catusse J, Wollner S, Leick M, Schrottner P, Schraufstatter I, Burger M. Attenuation of cxcr4 responses by ccl18 in acute lymphocytic leukemia b cells. J Cell Physiol. 2010;225:792–800.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu Y, Liu Y, Qian Y, Dai X, Yang L, Chen J, et al. Research on the efficacy of celastrus orbiculatus in suppressing tgf-beta1-induced epithelial-mesenchymal transition by inhibiting hsp27 and tnf-alpha-induced nf-kappa b/Snail signaling pathway in human gastric adenocarcinoma. BMC Complement Altern Med. 2014;14:433.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yang Y, Li Y, Wang K, Wang Y, Yin W, Li L. P38/nf-kappab/snail pathway is involved in caffeic acid-induced inhibition of cancer stem cells-like properties and migratory capacity in malignant human keratinocyte. PLoS One. 2013;8, e58915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from Guangdong Provincial Department of Science and Technology (2009B080701088), Guangzhou Bureau of Science and Information Technology (2013 J4100059), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University, and Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology.

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    Authors and Affiliations

    1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

      Zeyu Lin, Wenbin Li, Heyun Zhang, Wei Wu, Yaorong Peng, Yunjie Zeng, Jie Wang & Nengtai Ouyang

    2. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

      Zeyu Lin, Wenbin Li, Heyun Zhang, Yaorong Peng & Jie Wang

    3. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

      Wei Wu

    4. Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

      Yunjie Zeng & Nengtai Ouyang

    5. Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China

      Yunle Wan

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    1. Zeyu Lin
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    Correspondence to Nengtai Ouyang.

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    The study was performed in accordance with the policies of the Institutional Research Ethics Committee of Sun Yat-Sen Memorial Hospital.

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    Informed consents were obtained from the patients by BioBank, and the patient’s personally identifiable information such as names, addresses, and contact information were removed.

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    Zeyu Lin and Wenbin Li contributed equally to this work.

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    Lin, Z., Li, W., Zhang, H. et al. CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma. Tumor Biol. 37, 3461–3468 (2016). https://doi.org/10.1007/s13277-015-4172-x

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    • DOI: https://doi.org/10.1007/s13277-015-4172-x

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