Research progress of hypoxia microenvironment in hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DONG Liqian , SHEN Benqiang ,  MA Yong

Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P. R. China;

Corresponding author：

MA Yong, Email: doctormy80@163.com

Keywords：

hepatocellular carcinoma; tumor microenvironment; hypoxia

DOI：

10.7507/1007-9424.201804036

Video：

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Objective To investigate relationship between hypoxia microenvironment and occurrence and development of hepatocellular carcinoma (HCC). Method The relevant literatures on researches of the relationship between the hypoxic microenvironment and the HCC were review and analyzed. Results The hypoxia microenvironment played an important role in inducing the drug resistance and angiogenesis of the HCC cells, and it was an important factor of affecting the ability of tumor metabolism, invasion, and migration. The hypoxia microenvironment could up-regulate the expression of hypoxia-inducible factors (HIFs) and promote its transcriptional activity, promote the expression of the vascular endothelial growth factor gene, and regulate the neovascularization in the tumor. Among them, the HIF-1α played a major role in regulating the angiogenesis, immune escape, tumor invasion and metastasis-related gene expression, participating in the glycolysis, regulating lysyl oxidase 2 and thus regulated epithelial-mesenchymal transition, then promoted the invasion and metastasis of the HCC; HIF-2α was a key regulator of the malignant phenotype involving in the cell proliferation, angiogenesis, apoptosis, metabolism, metastasis, and resistance to chemotherapy. The hypoxia microenvironment posed some difficulties for the treatment of HCC, but it was also a potential therapeutic breakthrough. Conclusion Hypoxia microenvironment can promote invasion and metastasis of HCC through various mechanisms, which provides new targets and strategies for clinical treatment of HCC.

Citation： DONG Liqian, SHEN Benqiang, MA Yong. Research progress of hypoxia microenvironment in hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(10): 1254-1258. doi: 10.7507/1007-9424.201804036 Copy

1.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2.	Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett, 2015, 368(1): 7-13.
3.	Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget, 2017, 8(28): 46691-46703.
4.	Hu B, Tang WG, Fan J, et al. Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation. Oncol Lett, 2018, 15(1): 467-474.
5.	Ju C, Colgan SP, Eltzschig HK. Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl), 2016, 94(6): 613-627.
6.	Choi SH, Park JY. Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference. Cancer Cell Int, 2017, 17: 3.
7.	于天池, 唐波. 缺氧诱导因子 1 和缺氧诱导因子 2 抑制剂靶向治疗癌症的研究进展. 医学综述, 2017, 23(7): 1305-1309, 1315.
8.	Sun YL, Cai JQ, Liu F, et al. Aberrant expression of peroxiredoxin 1 and its clinical implications in liver cancer. World J Gastroenterol, 2015, 21(38): 10840-10852.
9.	Zhan Y, Zheng N, Teng F, et al. MiR-199a/b-5p inhibits hepatocellular carcinoma progression by post-transcriptionally suppressing ROCK1. Oncotarget, 2017, 8(40): 67169-67180.
10.	Liu Z, Tu K, Wang Y, et al. Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling. Cell Physiol Biochem, 2017, 44(5): 1856-1868.
11.	Jiang J, Wang GZ, Wang Y, et al. Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res, 2018, 367(1): 81-88.
12.	Buschauer S, Koch A, Wiggermann P, et al. Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment. Oncol Lett, 2018, 15(4): 4635-4640.
13.	Zhang Y, Lu Y, Zhang C, et al. FSCN-1 increases doxorubicin resistance in hepatocellular carcinoma through promotion of epithelial-mesenchymal transition. Int J Oncol, 2018 Mar 20. doi: 10.3892/ijo.2018.4327.
14.	Dong XF, Liu TQ, Zhi XT, et al. COX-2/PGE2 axis regulates hif2α activity to promote hepatocellular carcinoma hypoxic response and reduce the sensitivity of sorafenib treatment. Clin Cancer Res, 2018, 24(13): 3204-3216.
15.	Guo J, Wang B, Fu Z, et al. Hypoxic microenvironment induces EMT and upgrades stem-like properties of gastric cancer cells. Technol Cancer Res Treat, 2016, 15(1): 60-68.
16.	Tang Y, Wang R, Zhang Y, et al. Co-upregulation of 14-3-3ζ and p-Akt is associated with oncogenesis and recurrence of hepatocellular carcinoma. Cell Physiol Biochem, 2018, 45(3): 1097-1107.
17.	Tang Y, Liu S, Li N, et al. 14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α. Oncotarget, 2016, 7(13): 15854-15867.
18.	Wang K, Duan C, Zou X, et al. Increased mediator complex subunit 15 expression is associated with poor prognosis in hepatocellular carcinoma. Oncol Lett, 2018, 15(4): 4303-4313.
19.	Lu Y, Sui J, Liu Y, et al. Association between hypoxia-inducible factor-1α gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case-control study. Gene, 2015, 564(1): 96-100.
20.	Semenza GL. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta, 2016, 1863(3): 382-391.
21.	Miao S, Wang SM, Cheng X, et al. Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor. Cancer Cell Int, 2017, 17: 119.
22.	Ibrahim AA, Schmithals C, Kowarz E, et al. Hypoxia causes downregulation of dicer in hepatocellular carcinoma, which is required for upregulation of hypoxia-inducible factor 1α and epithelial-mesenchymal transition. Clin Cancer Res, 2017, 23(14): 3896-3905.
23.	Wang M, Zhao X, Zhu D, et al. HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. J Exp Clin Cancer Res, 2017, 36(1): 60.
24.	Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis, 2015, 6: e1600.
25.	Cannito S, Turato C, Paternostro C, et al. Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells. Oncotarget, 2015, 6(4): 2206-2221.
26.	Shneor D, Folberg R, Pe’er J, et al. Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma. Cancer Gene Ther, 2017, 24(2): 64-74.
27.	Sun HX, Xu Y, Yang XR, et al. Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway. Hepatology, 2013, 57(3): 1088-1097.
28.	Yang SL, Liu LP, Niu L, et al. Downregulation and pro-apoptotic effect of hypoxia-inducible factor 2 alpha in hepatocellular carcinoma. Oncotarget, 2016, 7(23): 34571-34581.
29.	Jiang L, Liu QL, Liang QL, et al. Association of PHD3 and HIF2α gene expression with clinicopathological characteristics in human hepatocellular carcinoma. Oncol Lett, 2018, 15(1): 545-551.
30.	Janaszak-Jasiecka A, Bartoszewska S, Kochan K, et al. miR-429 regulates the transition between hypoxia-inducible factor (HIF)1A and HIF3A expression in human endothelial cells. Sci Rep, 2016, 6: 22775.
31.	Maynard MA, Evans AJ, Shi W, et al. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle, 2007, 6(22): 2810-2816.
32.	Payne SJ, Jones L. Influence of the tumor microenvironment on angiogenesis. Future Oncol, 2011, 7(3): 395-408.
33.	刘锋, 李杰. HIF-2α 通过 Wnt/β-catenin 信号通路介导肝细胞肝癌对索拉菲尼耐药机理的实验研究. 山东大学, 2015.
34.	Nauta TD, van den Broek M, Gibbs S, et al. Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis, 2017, 20(1): 39-54.
35.	Nahm JH, Rhee H, Kim H, et al. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. Oncotarget, 2017, 8(59): 99359-99371.
36.	Shi S, Rao Q, Zhang C, et al. Dendritic cells pulsed with exosomes in combination with PD-1 antibody increase the efficacy of sorafenib in hepatocellular carcinoma model. Transl Oncol, 2018, 11(2): 250-258.
37.	Civenni G, Malek A, Albino D, et al. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer Res, 2013, 73(22): 6816-6827.
38.	Xu J, Zheng L, Chen J, et al. Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis, 2017, 8(10): e3095.
39.	Tang N, Shi L, Yu Z, et al. Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway. Oncotarget, 2016, 7(3): 3533-3547.
40.	Maghsoudlou A, Meyer RD, Rezazadeh K, et al. RNF121 inhibits angiogenic growth factor signaling by restricting cell surface expression of VEGFR-2. Traffic, 2016, 17(3): 289-300.
41.	Li YL, Zhang NY, Hu X, et al. Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1α under hypoxia. Biochem Biophys Res Commun, 2018, 498(3): 481-486.
42.	Prieto-Domínguez N, Méndez-Blanco C, Carbajo-Pescador S, et al. Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy. Oncotarget, 2017, 8(53): 91402-91414.

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2. Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett, 2015, 368(1): 7-13.
3. Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget, 2017, 8(28): 46691-46703.
4. Hu B, Tang WG, Fan J, et al. Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation. Oncol Lett, 2018, 15(1): 467-474.
5. Ju C, Colgan SP, Eltzschig HK. Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl), 2016, 94(6): 613-627.
6. Choi SH, Park JY. Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference. Cancer Cell Int, 2017, 17: 3.
7. 于天池, 唐波. 缺氧诱导因子 1 和缺氧诱导因子 2 抑制剂靶向治疗癌症的研究进展. 医学综述, 2017, 23(7): 1305-1309, 1315.
8. Sun YL, Cai JQ, Liu F, et al. Aberrant expression of peroxiredoxin 1 and its clinical implications in liver cancer. World J Gastroenterol, 2015, 21(38): 10840-10852.
9. Zhan Y, Zheng N, Teng F, et al. MiR-199a/b-5p inhibits hepatocellular carcinoma progression by post-transcriptionally suppressing ROCK1. Oncotarget, 2017, 8(40): 67169-67180.
10. Liu Z, Tu K, Wang Y, et al. Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling. Cell Physiol Biochem, 2017, 44(5): 1856-1868.
11. Jiang J, Wang GZ, Wang Y, et al. Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res, 2018, 367(1): 81-88.
12. Buschauer S, Koch A, Wiggermann P, et al. Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment. Oncol Lett, 2018, 15(4): 4635-4640.
13. Zhang Y, Lu Y, Zhang C, et al. FSCN-1 increases doxorubicin resistance in hepatocellular carcinoma through promotion of epithelial-mesenchymal transition. Int J Oncol, 2018 Mar 20. doi: 10.3892/ijo.2018.4327.
14. Dong XF, Liu TQ, Zhi XT, et al. COX-2/PGE2 axis regulates hif2α activity to promote hepatocellular carcinoma hypoxic response and reduce the sensitivity of sorafenib treatment. Clin Cancer Res, 2018, 24(13): 3204-3216.
15. Guo J, Wang B, Fu Z, et al. Hypoxic microenvironment induces EMT and upgrades stem-like properties of gastric cancer cells. Technol Cancer Res Treat, 2016, 15(1): 60-68.
16. Tang Y, Wang R, Zhang Y, et al. Co-upregulation of 14-3-3ζ and p-Akt is associated with oncogenesis and recurrence of hepatocellular carcinoma. Cell Physiol Biochem, 2018, 45(3): 1097-1107.
17. Tang Y, Liu S, Li N, et al. 14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α. Oncotarget, 2016, 7(13): 15854-15867.
18. Wang K, Duan C, Zou X, et al. Increased mediator complex subunit 15 expression is associated with poor prognosis in hepatocellular carcinoma. Oncol Lett, 2018, 15(4): 4303-4313.
19. Lu Y, Sui J, Liu Y, et al. Association between hypoxia-inducible factor-1α gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case-control study. Gene, 2015, 564(1): 96-100.
20. Semenza GL. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta, 2016, 1863(3): 382-391.
21. Miao S, Wang SM, Cheng X, et al. Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor. Cancer Cell Int, 2017, 17: 119.
22. Ibrahim AA, Schmithals C, Kowarz E, et al. Hypoxia causes downregulation of dicer in hepatocellular carcinoma, which is required for upregulation of hypoxia-inducible factor 1α and epithelial-mesenchymal transition. Clin Cancer Res, 2017, 23(14): 3896-3905.
23. Wang M, Zhao X, Zhu D, et al. HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. J Exp Clin Cancer Res, 2017, 36(1): 60.
24. Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis, 2015, 6: e1600.
25. Cannito S, Turato C, Paternostro C, et al. Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells. Oncotarget, 2015, 6(4): 2206-2221.
26. Shneor D, Folberg R, Pe’er J, et al. Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma. Cancer Gene Ther, 2017, 24(2): 64-74.
27. Sun HX, Xu Y, Yang XR, et al. Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway. Hepatology, 2013, 57(3): 1088-1097.
28. Yang SL, Liu LP, Niu L, et al. Downregulation and pro-apoptotic effect of hypoxia-inducible factor 2 alpha in hepatocellular carcinoma. Oncotarget, 2016, 7(23): 34571-34581.
29. Jiang L, Liu QL, Liang QL, et al. Association of PHD3 and HIF2α gene expression with clinicopathological characteristics in human hepatocellular carcinoma. Oncol Lett, 2018, 15(1): 545-551.
30. Janaszak-Jasiecka A, Bartoszewska S, Kochan K, et al. miR-429 regulates the transition between hypoxia-inducible factor (HIF)1A and HIF3A expression in human endothelial cells. Sci Rep, 2016, 6: 22775.
31. Maynard MA, Evans AJ, Shi W, et al. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle, 2007, 6(22): 2810-2816.
32. Payne SJ, Jones L. Influence of the tumor microenvironment on angiogenesis. Future Oncol, 2011, 7(3): 395-408.
33. 刘锋, 李杰. HIF-2α 通过 Wnt/β-catenin 信号通路介导肝细胞肝癌对索拉菲尼耐药机理的实验研究. 山东大学, 2015.
34. Nauta TD, van den Broek M, Gibbs S, et al. Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis, 2017, 20(1): 39-54.
35. Nahm JH, Rhee H, Kim H, et al. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. Oncotarget, 2017, 8(59): 99359-99371.
36. Shi S, Rao Q, Zhang C, et al. Dendritic cells pulsed with exosomes in combination with PD-1 antibody increase the efficacy of sorafenib in hepatocellular carcinoma model. Transl Oncol, 2018, 11(2): 250-258.
37. Civenni G, Malek A, Albino D, et al. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer Res, 2013, 73(22): 6816-6827.
38. Xu J, Zheng L, Chen J, et al. Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis, 2017, 8(10): e3095.
39. Tang N, Shi L, Yu Z, et al. Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway. Oncotarget, 2016, 7(3): 3533-3547.
40. Maghsoudlou A, Meyer RD, Rezazadeh K, et al. RNF121 inhibits angiogenic growth factor signaling by restricting cell surface expression of VEGFR-2. Traffic, 2016, 17(3): 289-300.
41. Li YL, Zhang NY, Hu X, et al. Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1α under hypoxia. Biochem Biophys Res Commun, 2018, 498(3): 481-486.
42. Prieto-Domínguez N, Méndez-Blanco C, Carbajo-Pescador S, et al. Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy. Oncotarget, 2017, 8(53): 91402-91414.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress of hypoxia microenvironment in hepatocellular carcinoma

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