Research Progress of Regulation of Hypoxia-mediated Signaling Pathways on Epithelial-Mesenchymal Transition of Tumor Cells_Journal of Biomedical Engineering

Authors：

CHENCan ^1,2 , ZHANGXiaomei ^1,2 , YANGLi ^1,2 ,  LuYonggang ^1,2

1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, China;
2. ‘111’ Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China;

Corresponding author：

LuYonggang, Email: yglv@cqu.edu.cn

Keywords：

tumor; hypoxia; epithelial-mesenchymal transition(EMT); hypoxia inducible factor; signaling pathway

DOI：

10.7507/1001-5515.20160096

Video：

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Abstract Full text Figures/Tables Video References Cited by

Hypoxic microenvironment always exists in solid tumors, and it closely relates to the development and metastasis of solid tumor. As a main transcription factor responding to hypoxic environment, hypoxia-inducible factor (HIF) can promote tumor cell proliferation, survival, angiogenesis, and epithelial-mesenchymal transition (EMT), etc. EMT is a biological process that epithelial phenotype was transformed into mesenchymal phenotype, which is mainly associated with its signaling pathways, transcription factors, inflammatory factors and miRNAs, and plays a vital role in tumor invasion and metastasis. This paper summarizes the effects of hypoxia signaling pathway, Wnt/β-catenin signaling pathway, Notch signaling pathway, NF-κB signaling pathway, Hedgehog (Hh) signaling pathway and PI3K/Akt signaling pathway on the EMT of tumor cells.

Citation： CHENCan, ZHANGXiaomei, YANGLi, LuYonggang. Research Progress of Regulation of Hypoxia-mediated Signaling Pathways on Epithelial-Mesenchymal Transition of Tumor Cells. Journal of Biomedical Engineering, 2016, 33(3): 575-582. doi: 10.7507/1001-5515.20160096 Copy

1.	THOMLINSON R H, GRAY L H. The histological structure of some human lung cancers and the possible implications for radiotherapy[J]. Br J Cancer, 1955, 9(4):539-549.
2.	MORIFUJI Y, ONISHI H, IWASAKI H, et al. Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling[J]. Cancer Sci, 2014, 105(3):324-333.
3.	JUSTUS C R, SANDERLIN E J, YANG L V. Molecular connections between cancer cell metabolism and the tumor microenvironment[J]. Int J Mol Sci, 2015, 16(5):11055-11086.
4.	LIN N U, FREEDMAN R A, RAMAKRISHNA N, et al. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2(HER2)-positive breast cancer brain metastases[J]. Breast Cancer Res Treat, 2013, 142(2):405-414.
5.	SADRI N, ZHANG P J. Hypoxia-inducible factors:mediators of cancer progression; prognostic and therapeutic targets in soft tissue sarcomas[J]. Cancers (Basel), 2013, 5(2):320-333.
6.	刘志娴, 魏尔清,卢韵碧.上皮-间质转化在肿瘤发生发展中的作用研究进展[J].浙江大学学报(医学版),2015(2):211-216.
7.	LAMOUILLE S, XU J, DERYNCK R. Molecular mechanisms of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3):178-196.
8.	CHEUNG S Y, BOEY Y J, KOH V C, et al. Role of epithelial-mesenchymal transition markers in triple-negative breast cancer[J]. Breast cancer Res Treat, 2015, 152(3):489-498.
9.	XING R-c, ZHENG J, ZHENG W-h, et al. Relevance of E-cadherin expression to EGFR-TKI molecular targeted therapy sensitivity/resistance and its clinical significance[J]. Genet Mol Res, 2015, 14(2):5785-5792.
10.	SU Y J, CHANG Y W, LIN W H, et al. An aberrant nuclear localization of E-cadherin is a potent inhibitor of Wnt/β-catenin-elicited promotion of the cancer stem cell phenotype[J]. Oncogenesis, 2015, 4:e157.
11.	PARK K S, DUBON M J, GUMBINER B M. N-cadherin mediates the migration of MCF-10A cells undergoing bone morphogenetic protein 4-mediated epithelial mesenchymal transition[J]. Tumour Biol, 2015, 36(5):3549-3556.
12.	COSTA L C, LEITE C F, CARDOSO S V, et al. Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma[J]. J Appl Oral Sci, 2015, 23(2):169-178.
13.	CHEN Lijun, YE Hong, ZHANG Qian, et al. Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells[J]. Toxicol Appl Pharmacol, 2015, 283(2):75-82.
14.	FAN Fan, SAMUEL S, EVANS K W, et al. Overexpression of snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells[J]. Cancer Med, 2012, 1(1):5-16.
15.	FRISCH S M, SCHALLER M, CIEPLY B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis[J]. J Cell Sci, 2013, 126(Pt 1):21-29.
16.	MITRA A, MISHRA L, LI Shu-lin. EMT, CTCs and CSCs in tumor relapse and drug-resistance[J]. Cancer Res, 2015, 6(13):10697-10711.
17.	LUO Dongjun, WANG Zhongxia, WU Junyi, et al. The role of hypoxia inducible factor-1 in hepatocellular carcinoma[J]. Biomed Res Int, 2014:409272.
18.	HUANG De, LI Chenchen, ZHANG Huafeng. Hypoxia and cancer cell metabolism[J]. Acta Biochim Biophys Sin (Shanghai), 2014, 46(3):214-219.
19.	AGAOGLU O K, AGAOGLU A R, GUZELOGLU A, et al. Expression of hypoxia-inducible factors and vascular endothelial growth factor during pregnancy in the feline uterus[J]. Theriogenology, 2015, 84(1):24-33.
20.	BERRA E, BENIZRI E, GINOUVÈS A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia[J]. EMBO J, 2003, 22(16):4082-4090.
21.	BAO Bin, AZMI A S, ALI Shadan, et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness[J]. Biochim Biophys Acta, 2012, 1826(2):272-296.
22.	王永兴, 姜永光,罗勇,等.缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响[J].首都医科大学学报,2014,35(3):278-283.
23.	BOCCA C, IEVOLELLA M, AUTELLI R, et al. Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness[J]. Expert Opin Ther Targets, 2014, 18(2):121-135.
24.	LIANG Jun, ZHANG Zhaoqiang, LIANG Lizhong, et al. HIF-1α regulated tongue squamous cell carcinoma cell growth via regulating VEGF expression in a xenograft model[J]. Annals of translational medicine, 2014, 2(9):92.
25.	LIEN W H, FUCHS E. Wnt some lose some:transcriptional governance of stem cells by Wnt/β-catenin signaling[J]. Genes Dev, 2014, 28(14):1517-1532.
26.	LIU Hao, YIN Jiang, WANG Hongsheng, et al. FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate Cancer cells[J]. Cell Signal, 2015, 27(3):510-518.
27.	YANG Ning, HUI Lian, WANG Yan, et al. Overexpression of SOX2 promotes migration, invasion, and epithelial-mesenchymal transition through the Wnt/β-catenin pathway in laryngeal cancer Hep-2 cells[J]. Tumour Biol, 2014, 35(8):7965-7973.
28.	NOPPARAT J, ZHANG J, LU J-p, et al. δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming[J]. Oncogene, 2015, 34(12):1542-1552.
29.	ZHANG Qi, BAI Xueli, CHEN Wei, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling[J]. Carcinogenesis, 2013, 34(5):962-973.
30.	WANG Chenhui, GUO Xingting, XI Rongwen. EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells[J]. Cell Res, 2014, 24(5):610-627.
31.	MEI Hongjun, YU Ling, JI Peng, et al. Doxorubicin activates the Notch signaling pathway in osteosarcoma[J]. Oncol Lett, 2015, 9(6):2905-2909.
32.	TOHDA S. NOTCH signaling roles in acute myeloid leukemia cell growth and interaction with other stemness-related signals[J]. Anticancer Res, 2014, 34(11):6259-6264.
33.	TIAN Quan, XUE Yan, ZHENG Wei, et al. Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling[J]. Int J Oncol, 2015, 47(2):728-738.
34.	ASNAGHI L, LIN M H, LIM K S, et al. Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation[J]. PLoS One, 2014, 9(8):e105372.
35.	CHENG Yao, ZHAO Kai, LI Guojun, et al. Oroxylin A inhibits hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway[J]. Anticancer Drugs, 2014, 25(7):778-789.
36.	GABALLAH H H, ZAKARIA S S, ISMAIL S A. Activity and expression pattern of NF-κB/P65 in peripheral blood from hepatocellular carcinoma patients-link to hypoxia inducible factor-1α[J]. Asian Pac J Cancer Prev, 2014, 15(16):6911-6917.
37.	TAFANI M, DE SANTIS E, COPPOLA L, et al. Bridging hypoxia, inflammation and estrogen receptors in thyroid cancer progression[J]. Biomed Pharmacother, 2014, 68(1):1-5.
38.	SEN D, CHAPLA A, WALTER N, et al. Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia[J]. J Thromb Haemost, 2013, 11(2):293-306.
39.	SCHOLZ C C, CAVADAS M A, TAMBUWALA M M, et al. Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways[J]. Proc Natl Acad Sci U S A, 2013, 110(46):18490-18495.
40.	BANDARRA D, BIDDLESTONE J, MUDIE S, et al. HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals[J]. Dis Model Mech, 2015, 8(2):169-181.
41.	XUE Jing, LI Xuebing, JIAO Shi, et al. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity[J]. Gastroenterology, 2010, 138(2):606-615.
42.	BANDARRA D, BIDDLESTONE J, MUDIE S, et al. Hypoxia activates IKK-NF-κB and the immune response in Drosophila melanogaster[J]. Biosci Rep, 2014, 34(4):e00127.
43.	BENDINELLI P, MATTEUCCI E, MARONI P, et al. NF-kappaB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells[J]. Mol Cancer Res, 2009, 7(8):1328-1341.
44.	HU Liping, LIN Xiangyang, LU Hong, et al. An overview of hedgehog signaling in fibrosis[J]. Mol Pharmacol, 2015, 87(2):174-182.
45.	LEI Jianjun, MA Jiguang, MA Qingyong, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner[J]. Mol Cancer, 2013, 12:66.
46.	ONISHI H, KAI M, ODATE S, et al. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic Cancer[J]. Cancer Sci, 2011, 102(6):1144-1150.
47.	CHAUDARY N, PINTILIE M, HEDLEY D, et al. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation[J]. Cancer, 2012, 118(12):3105-3115.
48.	ZHANG Xiangliang, SHI Huijuan, TANG Hongsheng, et al. miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway[J]. Int J Mol Med, 2015, 35(5):1301-1308.
49.	LI Yanyan, JIA Li, LIU Chen, et al. Axl as a downstream effector of TGF-β1 via PI3K/Akt-PAK1 signaling pathway promotes tumor invasion and chemoresistance in breast carcinoma[J]. Tumour Biol, 2015, 36(2):1115-1127.
50.	RUBASHKIN M G, CASSEREAU L, BAINER R, et al. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate[J]. Cancer Res, 2014, 74(17):4597-4611.
51.	CHANG L, GRAHAM P H, HAO J, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance[J]. Cell Death Dis, 2013, 4(10):e875.
52.	SUN Guixiang, ZHOU Yanni, LI Hongsheng, et al. Over-expression of microRNA-494 up-regulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis[J]. J Biomed Sci, 2013, 20:100.
53.	LI Jie, ZHANG Chao, JIANG Hongchuan, et al. Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast Cancer growth[J]. Onco Targets Ther, 2015, 8:427-435.
54.	LEE Sun-hee, JEE J G, BAE J S, et al. A group of novel HIF-1α inhibitors, glyceollins, blocks HIF-1α synthesis and decreases its stability via inhibition of the PI3K/AKT/mTOR pathway and Hsp90 binding[J]. J Cell Physiol, 2015, 230(4):853-862.
55.	ATAWIA R T, MOSLI H H, TADROS M G, et al. Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia:emphasis on PTEN, HIF-1α, and NF-κB[J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(12):1131-1140.

1. THOMLINSON R H, GRAY L H. The histological structure of some human lung cancers and the possible implications for radiotherapy[J]. Br J Cancer, 1955, 9(4):539-549.
2. MORIFUJI Y, ONISHI H, IWASAKI H, et al. Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling[J]. Cancer Sci, 2014, 105(3):324-333.
3. JUSTUS C R, SANDERLIN E J, YANG L V. Molecular connections between cancer cell metabolism and the tumor microenvironment[J]. Int J Mol Sci, 2015, 16(5):11055-11086.
4. LIN N U, FREEDMAN R A, RAMAKRISHNA N, et al. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2(HER2)-positive breast cancer brain metastases[J]. Breast Cancer Res Treat, 2013, 142(2):405-414.
5. SADRI N, ZHANG P J. Hypoxia-inducible factors:mediators of cancer progression; prognostic and therapeutic targets in soft tissue sarcomas[J]. Cancers (Basel), 2013, 5(2):320-333.
6. 刘志娴, 魏尔清,卢韵碧.上皮-间质转化在肿瘤发生发展中的作用研究进展[J].浙江大学学报(医学版),2015(2):211-216.
7. LAMOUILLE S, XU J, DERYNCK R. Molecular mechanisms of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3):178-196.
8. CHEUNG S Y, BOEY Y J, KOH V C, et al. Role of epithelial-mesenchymal transition markers in triple-negative breast cancer[J]. Breast cancer Res Treat, 2015, 152(3):489-498.
9. XING R-c, ZHENG J, ZHENG W-h, et al. Relevance of E-cadherin expression to EGFR-TKI molecular targeted therapy sensitivity/resistance and its clinical significance[J]. Genet Mol Res, 2015, 14(2):5785-5792.
10. SU Y J, CHANG Y W, LIN W H, et al. An aberrant nuclear localization of E-cadherin is a potent inhibitor of Wnt/β-catenin-elicited promotion of the cancer stem cell phenotype[J]. Oncogenesis, 2015, 4:e157.
11. PARK K S, DUBON M J, GUMBINER B M. N-cadherin mediates the migration of MCF-10A cells undergoing bone morphogenetic protein 4-mediated epithelial mesenchymal transition[J]. Tumour Biol, 2015, 36(5):3549-3556.
12. COSTA L C, LEITE C F, CARDOSO S V, et al. Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma[J]. J Appl Oral Sci, 2015, 23(2):169-178.
13. CHEN Lijun, YE Hong, ZHANG Qian, et al. Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells[J]. Toxicol Appl Pharmacol, 2015, 283(2):75-82.
14. FAN Fan, SAMUEL S, EVANS K W, et al. Overexpression of snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells[J]. Cancer Med, 2012, 1(1):5-16.
15. FRISCH S M, SCHALLER M, CIEPLY B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis[J]. J Cell Sci, 2013, 126(Pt 1):21-29.
16. MITRA A, MISHRA L, LI Shu-lin. EMT, CTCs and CSCs in tumor relapse and drug-resistance[J]. Cancer Res, 2015, 6(13):10697-10711.
17. LUO Dongjun, WANG Zhongxia, WU Junyi, et al. The role of hypoxia inducible factor-1 in hepatocellular carcinoma[J]. Biomed Res Int, 2014:409272.
18. HUANG De, LI Chenchen, ZHANG Huafeng. Hypoxia and cancer cell metabolism[J]. Acta Biochim Biophys Sin (Shanghai), 2014, 46(3):214-219.
19. AGAOGLU O K, AGAOGLU A R, GUZELOGLU A, et al. Expression of hypoxia-inducible factors and vascular endothelial growth factor during pregnancy in the feline uterus[J]. Theriogenology, 2015, 84(1):24-33.
20. BERRA E, BENIZRI E, GINOUVÈS A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia[J]. EMBO J, 2003, 22(16):4082-4090.
21. BAO Bin, AZMI A S, ALI Shadan, et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness[J]. Biochim Biophys Acta, 2012, 1826(2):272-296.
22. 王永兴, 姜永光,罗勇,等.缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响[J].首都医科大学学报,2014,35(3):278-283.
23. BOCCA C, IEVOLELLA M, AUTELLI R, et al. Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness[J]. Expert Opin Ther Targets, 2014, 18(2):121-135.
24. LIANG Jun, ZHANG Zhaoqiang, LIANG Lizhong, et al. HIF-1α regulated tongue squamous cell carcinoma cell growth via regulating VEGF expression in a xenograft model[J]. Annals of translational medicine, 2014, 2(9):92.
25. LIEN W H, FUCHS E. Wnt some lose some:transcriptional governance of stem cells by Wnt/β-catenin signaling[J]. Genes Dev, 2014, 28(14):1517-1532.
26. LIU Hao, YIN Jiang, WANG Hongsheng, et al. FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate Cancer cells[J]. Cell Signal, 2015, 27(3):510-518.
27. YANG Ning, HUI Lian, WANG Yan, et al. Overexpression of SOX2 promotes migration, invasion, and epithelial-mesenchymal transition through the Wnt/β-catenin pathway in laryngeal cancer Hep-2 cells[J]. Tumour Biol, 2014, 35(8):7965-7973.
28. NOPPARAT J, ZHANG J, LU J-p, et al. δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming[J]. Oncogene, 2015, 34(12):1542-1552.
29. ZHANG Qi, BAI Xueli, CHEN Wei, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling[J]. Carcinogenesis, 2013, 34(5):962-973.
30. WANG Chenhui, GUO Xingting, XI Rongwen. EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells[J]. Cell Res, 2014, 24(5):610-627.
31. MEI Hongjun, YU Ling, JI Peng, et al. Doxorubicin activates the Notch signaling pathway in osteosarcoma[J]. Oncol Lett, 2015, 9(6):2905-2909.
32. TOHDA S. NOTCH signaling roles in acute myeloid leukemia cell growth and interaction with other stemness-related signals[J]. Anticancer Res, 2014, 34(11):6259-6264.
33. TIAN Quan, XUE Yan, ZHENG Wei, et al. Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling[J]. Int J Oncol, 2015, 47(2):728-738.
34. ASNAGHI L, LIN M H, LIM K S, et al. Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation[J]. PLoS One, 2014, 9(8):e105372.
35. CHENG Yao, ZHAO Kai, LI Guojun, et al. Oroxylin A inhibits hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway[J]. Anticancer Drugs, 2014, 25(7):778-789.
36. GABALLAH H H, ZAKARIA S S, ISMAIL S A. Activity and expression pattern of NF-κB/P65 in peripheral blood from hepatocellular carcinoma patients-link to hypoxia inducible factor-1α[J]. Asian Pac J Cancer Prev, 2014, 15(16):6911-6917.
37. TAFANI M, DE SANTIS E, COPPOLA L, et al. Bridging hypoxia, inflammation and estrogen receptors in thyroid cancer progression[J]. Biomed Pharmacother, 2014, 68(1):1-5.
38. SEN D, CHAPLA A, WALTER N, et al. Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia[J]. J Thromb Haemost, 2013, 11(2):293-306.
39. SCHOLZ C C, CAVADAS M A, TAMBUWALA M M, et al. Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways[J]. Proc Natl Acad Sci U S A, 2013, 110(46):18490-18495.
40. BANDARRA D, BIDDLESTONE J, MUDIE S, et al. HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals[J]. Dis Model Mech, 2015, 8(2):169-181.
41. XUE Jing, LI Xuebing, JIAO Shi, et al. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity[J]. Gastroenterology, 2010, 138(2):606-615.
42. BANDARRA D, BIDDLESTONE J, MUDIE S, et al. Hypoxia activates IKK-NF-κB and the immune response in Drosophila melanogaster[J]. Biosci Rep, 2014, 34(4):e00127.
43. BENDINELLI P, MATTEUCCI E, MARONI P, et al. NF-kappaB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells[J]. Mol Cancer Res, 2009, 7(8):1328-1341.
44. HU Liping, LIN Xiangyang, LU Hong, et al. An overview of hedgehog signaling in fibrosis[J]. Mol Pharmacol, 2015, 87(2):174-182.
45. LEI Jianjun, MA Jiguang, MA Qingyong, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner[J]. Mol Cancer, 2013, 12:66.
46. ONISHI H, KAI M, ODATE S, et al. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic Cancer[J]. Cancer Sci, 2011, 102(6):1144-1150.
47. CHAUDARY N, PINTILIE M, HEDLEY D, et al. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation[J]. Cancer, 2012, 118(12):3105-3115.
48. ZHANG Xiangliang, SHI Huijuan, TANG Hongsheng, et al. miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway[J]. Int J Mol Med, 2015, 35(5):1301-1308.
49. LI Yanyan, JIA Li, LIU Chen, et al. Axl as a downstream effector of TGF-β1 via PI3K/Akt-PAK1 signaling pathway promotes tumor invasion and chemoresistance in breast carcinoma[J]. Tumour Biol, 2015, 36(2):1115-1127.
50. RUBASHKIN M G, CASSEREAU L, BAINER R, et al. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate[J]. Cancer Res, 2014, 74(17):4597-4611.
51. CHANG L, GRAHAM P H, HAO J, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance[J]. Cell Death Dis, 2013, 4(10):e875.
52. SUN Guixiang, ZHOU Yanni, LI Hongsheng, et al. Over-expression of microRNA-494 up-regulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis[J]. J Biomed Sci, 2013, 20:100.
53. LI Jie, ZHANG Chao, JIANG Hongchuan, et al. Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast Cancer growth[J]. Onco Targets Ther, 2015, 8:427-435.
54. LEE Sun-hee, JEE J G, BAE J S, et al. A group of novel HIF-1α inhibitors, glyceollins, blocks HIF-1α synthesis and decreases its stability via inhibition of the PI3K/AKT/mTOR pathway and Hsp90 binding[J]. J Cell Physiol, 2015, 230(4):853-862.
55. ATAWIA R T, MOSLI H H, TADROS M G, et al. Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia:emphasis on PTEN, HIF-1α, and NF-κB[J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(12):1131-1140.

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