Study on the relationship between epithelial-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YAN Long ,  DAI Chaoliu

Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R.China;

Corresponding author：

DAI Chaoliu, Email: daicl@sj-hospital.org

Keywords：

epithelial-mesenchymal transition; tumor invasion and metastasis; tumor microenvironment; hepatocellular carcinoma; inflammatory factor

DOI：

10.7507/1007-9424.201609094

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To introduce the inflammatory microenvironment and epithelial-mesenchymal transition process of hepatocellular carcinoma, and review the relationship between them. Methods Domestic and international literatures were collected to summary the relationship between epithelial-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. Result Many inflammatory factors and viral gene encoding proteins in the inflammatory microenvironment play an important role in the process of epithelial-mesenchymal transition in hepatocellular carcinoma. Conclusions The inflammatory microenvironment of hepatocellular carcinoma is an indispensable role in the process of epithelial-mesenchymal transition. The inhibition and treatment of inflammatory microenvironment may play a more active role in the control of tumor invasion and metastasis.

Citation： YAN Long, DAI Chaoliu. Study on the relationship between epithelial-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(7): 885-889. doi: 10.7507/1007-9424.201609094 Copy

1.	Valcourt U, Carthy J, Okita Y, et al. Analysis of epithelial–mesenchymal transition induced by transforming growth factor β. Methods Mol Biol, 2016, 1344: 157-182.
2.	Wyckoff JB, Wang YR, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res, 2007, 67(6): 2649-2656.
3.	Wei Jiang, Pang XG, Wang Q, et al. Prognostic role of Twist, Slug, and Foxc2 expression in stage Ⅰ non-small-cell lung cancer after curative resection. Clin Lung Cancer, 2012, 13(4): 280-287.
4.	Chaw SY, Majeed AA, Dalley AJ, et al. Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and Vimentin—in oral squamous cell carcinogenesis and transformation. Oral Oncol, 2012, 48(10): 997-1006.
5.	Zhou Z, Zhang L, Xie B, et al. FOXC2 promotes chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition. Cancer Lett, 2015, 363(2): 137-145.
6.	Liu RY, Zeng YY, Lei Z, et al. JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol, 2014, 44(5): 1643-1651.
7.	Bao RF, Shu YJ, Hu YP, et al. miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and smad pathways in gallbladder carcinoma. Oncotarget, 2016, 7(16): 22339-22354.
8.	Wang SC, Chai DS, Chen CB, et al. HPIP promotes thyroid cancer cell growth, migration and EMT through activating PI3K/AKT signaling pathway. Biomed Pharmacother, 2015, 75: 33-39.
9.	Liu ZC, Chen XH, Song HX, et al. Snail regulated by PKC/GSK-3beta pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res, 2014, 358(2): 491-502.
10.	David CJ, Huang YH, Chen M, et al. TGF-β tumor suppression through a lethal EMT. Cell, 2016, 164(5): 1015-1030.
11.	Bastiaans J, van Meurs JC, van Holten-Neelen C, et al. Thrombin induces epithelial-mesenchymal transition and collagen production by retinal pigment epithelial cells via autocrine PDGF-receptor signaling. Invest Ophthalmol Vis Sci, 2013, 54(13): 8306-8314.
12.	Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013, 19(11): 1423-1437.
13.	Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett, 2015, 368(1): 7-13.
14.	Soucek L, Lawlor ER, Soto D, et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med, 2007, 13(10): 1211-1218.
15.	Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell, 2010, 140(2): 197-208.
16.	Wu J, Zhang J, Shen B, et al. Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition. J Exp Clin Cancer Res, 2015, 34: 116.
17.	Hatziapostolou M, Polytarchou C, Aggelidou, et al. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell, 2011, 147(6): 1233-1247.
18.	Zhao Z, Cheng X, Wang Y, et al. Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PLoS One, 2014, 9(4): e95884.
19.	Chen W, Gao Q, Han S, et al. The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour Biol, 2015, 36(2): 973-981.
20.	Yadav A, Kumar B, Datta J, et al. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res, 2011, 9(12): 1658-1667.
21.	Sullivan NJ, Sasser AK, Axel AE, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene, 2009, 28(33): 2940-2947.
22.	Huang W, Chen Z, Zhang L, et al. Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice. Gastroenterology, 2015, 149(4): 1053-1067.
23.	Fu XT, Dai Z, Song, et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol, 2015, 46(2): 587-596.
24.	Akiba J, Yano H, Ogasawara S, et al. Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol, 2001, 18(2): 257-264.
25.	Yu J, Ren X, Chen Y, et al. Dysfunctional activation of neurotensin/IL-8 pathway in hepatocellular carcinoma is associated with increased inflammatory response in microenvironment, more epithelial mesenchymal transition in cancer and worse prognosis in patients. PLoS One, 2013, 8(2): e56069.
26.	Fernando RI, Castillo MD, Litzinger M, et al. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res, 2011, 71(15): 5296-5306.
27.	Wang L, Tang C, Cao H, et al. Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells. Cancer Biol Ther, 2015, 16(8): 1220-1230.
28.	Yin J, Zeng F, Wu N, et al. Interleukin-8 promotes human ovarian cancer cell migration by epithelial-mesenchymal transition induction in vitro. Clin Transl Oncol, 2015, 17(5): 365-370.
29.	Zhu Y, Cheng Y, Guo YB, et al. Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion via the PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma. Oncotarget, 2015, 7(5): 5327-5341.
30.	Zhou B, Zhuang XM, Wang YY, et al. Tumor necrosis factor alpha induces myofibroblast differentiation in human tongue cancer and promotes invasiveness and angiogenesis via secretion of stromal cell-derived factor-1. Oral Oncol, 2015, 51(12): 1095-1102.
31.	Techasen A, Namwat N, Loilome W, et al. Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma. Med Oncol, 2012, 29(5): 3083-3091.
32.	Lv N, Gao Y, Guan H, et al. Inflammatory mediators, tumor necrosis factor-alpha and interferon-gamma, induce EMT in human PTC cell lines. Oncol Lett, 2015, 10(4): 2591-2597.
33.	Yu L, Sa N, Wang H, et al. Tumor necrosis factor alpha induces epithelial-mesenchymal transition and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. Oncol Rep, 2014, 31(1): 321-327.
34.	Wang H, Wang HS, Zhou BH, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One, 2013, 8(2): e56664.
35.	Kudo-Saito C, Shirako H, Ohike M, et al. CCL2 is critical for immunosuppression to promote cancer metastasis. Clin Exp Metastasis, 2013, 30(4): 393-405.
36.	Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med, 2004, 350(11): 1118-1129.
37.	Liu H, He H, Zhu Y, et al. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein. Cancer Sci, 2012, 103(12): 2072-2081.
38.	LU Q, Xiong Y, Cai L, et al. Hepatitis B virus X protein upregulates the transcription activity of zinc finger transcription factor SNAIl. Natl Med J China, 2009, 89(14): 990-993.
39.	Teng J, Wang X, Tang N, et al. HBx-dependent activation of Twist mediates STAT3 control of epithelium-mesenchymal transition of liver cells. J Cell Biochem, 2013, 114(5): 1097-1104.
40.	Yang SZ, Zhang LD, Zhang Y, et al. HBx protein induces EMT through c-Src activation in SMMC-7721 hepatoma cell line. Biochem Biophys Res Commun, 2009, 382(3): 555-560.
41.	Ha HL, Kwon T, Bak IS, et al. IGF-Ⅱ induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice. Oncotarget, 2016, 7(35): 56944-56957.
42.	Shin Kim S, Yeom S, Kwak J, et al. Hepatitis B virus X protein induces epithelial-mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47. J Gen Virol, 2016, 97(1): 134-143.
43.	Perez-Moreno MA, Locascio A, Rodrigo I, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem, 2001, 276(29): 27424-27431.
44.	Wang T, Jin Y, Wu Y, et al. High load hepatitis B virus replication inhibits hepatocellular carcinoma cell metastasis through regulation of epithelial-mesenchymal transition. Int J Infect Dis, 2014, 20: 37-41.

1. Valcourt U, Carthy J, Okita Y, et al. Analysis of epithelial–mesenchymal transition induced by transforming growth factor β. Methods Mol Biol, 2016, 1344: 157-182.
2. Wyckoff JB, Wang YR, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res, 2007, 67(6): 2649-2656.
3. Wei Jiang, Pang XG, Wang Q, et al. Prognostic role of Twist, Slug, and Foxc2 expression in stage Ⅰ non-small-cell lung cancer after curative resection. Clin Lung Cancer, 2012, 13(4): 280-287.
4. Chaw SY, Majeed AA, Dalley AJ, et al. Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and Vimentin—in oral squamous cell carcinogenesis and transformation. Oral Oncol, 2012, 48(10): 997-1006.
5. Zhou Z, Zhang L, Xie B, et al. FOXC2 promotes chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition. Cancer Lett, 2015, 363(2): 137-145.
6. Liu RY, Zeng YY, Lei Z, et al. JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol, 2014, 44(5): 1643-1651.
7. Bao RF, Shu YJ, Hu YP, et al. miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and smad pathways in gallbladder carcinoma. Oncotarget, 2016, 7(16): 22339-22354.
8. Wang SC, Chai DS, Chen CB, et al. HPIP promotes thyroid cancer cell growth, migration and EMT through activating PI3K/AKT signaling pathway. Biomed Pharmacother, 2015, 75: 33-39.
9. Liu ZC, Chen XH, Song HX, et al. Snail regulated by PKC/GSK-3beta pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res, 2014, 358(2): 491-502.
10. David CJ, Huang YH, Chen M, et al. TGF-β tumor suppression through a lethal EMT. Cell, 2016, 164(5): 1015-1030.
11. Bastiaans J, van Meurs JC, van Holten-Neelen C, et al. Thrombin induces epithelial-mesenchymal transition and collagen production by retinal pigment epithelial cells via autocrine PDGF-receptor signaling. Invest Ophthalmol Vis Sci, 2013, 54(13): 8306-8314.
12. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013, 19(11): 1423-1437.
13. Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett, 2015, 368(1): 7-13.
14. Soucek L, Lawlor ER, Soto D, et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med, 2007, 13(10): 1211-1218.
15. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell, 2010, 140(2): 197-208.
16. Wu J, Zhang J, Shen B, et al. Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition. J Exp Clin Cancer Res, 2015, 34: 116.
17. Hatziapostolou M, Polytarchou C, Aggelidou, et al. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell, 2011, 147(6): 1233-1247.
18. Zhao Z, Cheng X, Wang Y, et al. Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PLoS One, 2014, 9(4): e95884.
19. Chen W, Gao Q, Han S, et al. The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour Biol, 2015, 36(2): 973-981.
20. Yadav A, Kumar B, Datta J, et al. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res, 2011, 9(12): 1658-1667.
21. Sullivan NJ, Sasser AK, Axel AE, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene, 2009, 28(33): 2940-2947.
22. Huang W, Chen Z, Zhang L, et al. Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice. Gastroenterology, 2015, 149(4): 1053-1067.
23. Fu XT, Dai Z, Song, et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol, 2015, 46(2): 587-596.
24. Akiba J, Yano H, Ogasawara S, et al. Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol, 2001, 18(2): 257-264.
25. Yu J, Ren X, Chen Y, et al. Dysfunctional activation of neurotensin/IL-8 pathway in hepatocellular carcinoma is associated with increased inflammatory response in microenvironment, more epithelial mesenchymal transition in cancer and worse prognosis in patients. PLoS One, 2013, 8(2): e56069.
26. Fernando RI, Castillo MD, Litzinger M, et al. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res, 2011, 71(15): 5296-5306.
27. Wang L, Tang C, Cao H, et al. Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells. Cancer Biol Ther, 2015, 16(8): 1220-1230.
28. Yin J, Zeng F, Wu N, et al. Interleukin-8 promotes human ovarian cancer cell migration by epithelial-mesenchymal transition induction in vitro. Clin Transl Oncol, 2015, 17(5): 365-370.
29. Zhu Y, Cheng Y, Guo YB, et al. Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion via the PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma. Oncotarget, 2015, 7(5): 5327-5341.
30. Zhou B, Zhuang XM, Wang YY, et al. Tumor necrosis factor alpha induces myofibroblast differentiation in human tongue cancer and promotes invasiveness and angiogenesis via secretion of stromal cell-derived factor-1. Oral Oncol, 2015, 51(12): 1095-1102.
31. Techasen A, Namwat N, Loilome W, et al. Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma. Med Oncol, 2012, 29(5): 3083-3091.
32. Lv N, Gao Y, Guan H, et al. Inflammatory mediators, tumor necrosis factor-alpha and interferon-gamma, induce EMT in human PTC cell lines. Oncol Lett, 2015, 10(4): 2591-2597.
33. Yu L, Sa N, Wang H, et al. Tumor necrosis factor alpha induces epithelial-mesenchymal transition and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. Oncol Rep, 2014, 31(1): 321-327.
34. Wang H, Wang HS, Zhou BH, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One, 2013, 8(2): e56664.
35. Kudo-Saito C, Shirako H, Ohike M, et al. CCL2 is critical for immunosuppression to promote cancer metastasis. Clin Exp Metastasis, 2013, 30(4): 393-405.
36. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med, 2004, 350(11): 1118-1129.
37. Liu H, He H, Zhu Y, et al. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein. Cancer Sci, 2012, 103(12): 2072-2081.
38. LU Q, Xiong Y, Cai L, et al. Hepatitis B virus X protein upregulates the transcription activity of zinc finger transcription factor SNAIl. Natl Med J China, 2009, 89(14): 990-993.
39. Teng J, Wang X, Tang N, et al. HBx-dependent activation of Twist mediates STAT3 control of epithelium-mesenchymal transition of liver cells. J Cell Biochem, 2013, 114(5): 1097-1104.
40. Yang SZ, Zhang LD, Zhang Y, et al. HBx protein induces EMT through c-Src activation in SMMC-7721 hepatoma cell line. Biochem Biophys Res Commun, 2009, 382(3): 555-560.
41. Ha HL, Kwon T, Bak IS, et al. IGF-Ⅱ induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice. Oncotarget, 2016, 7(35): 56944-56957.
42. Shin Kim S, Yeom S, Kwak J, et al. Hepatitis B virus X protein induces epithelial-mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47. J Gen Virol, 2016, 97(1): 134-143.
43. Perez-Moreno MA, Locascio A, Rodrigo I, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem, 2001, 276(29): 27424-27431.
44. Wang T, Jin Y, Wu Y, et al. High load hepatitis B virus replication inhibits hepatocellular carcinoma cell metastasis through regulation of epithelial-mesenchymal transition. Int J Infect Dis, 2014, 20: 37-41.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Study on the relationship between epithelial-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

Abstract Full text Figures/Tables Video References Cited by

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