||The roles of dual specificity phosphatase-2 (DUSP2) in tumor progression and drug resistance
||Institute of Basic Medical Sciences
Hypoxia and constitutive activation of extracellular signal-regulated kinase (ERK) are well known factors that play roles in tumorigenesis and drug resistance in a variety of cancers. However, the underlying mechanism causing aberrant activation of ERK in the majority of cancers is still unclear. It has been reported that hypoxia can prevent apoptosis, promote cell invasion and even increase drug resistance by activating ERK signaling pathway through an unknown mechanism in cancer cells. Herein, we show that dual specificity phosphatase-2 (DUSP2), a mitogen-activated protein kinase (MAPK)-specific phosphatase is markedly reduced in many human cancers and its expression level is inversely correlated with cancer malignancy and with hypoxic index. To further investigate the effect of hypoxia on DUSP2 expression, we found that DUSP2 expressions are repressed by hypoxia in a variety of cancer cell lines. Moreover, hypoxia-repressed DUSP2 is mainly controlled at the transcriptional level by hypoxia-inducible factor-1 alpha (HIF-1 alpha) through a directly binding to the predicted hypoxia response element (HRE) located in DUSP2 promoter region (-100~-117). Suppression of DUSP2 by hypoxia leads to prolonged ERK phosphorylation and drug resistance. Restoration of DUSP2 expression under hypoxia not only inhibits abnormal ERK activation but also attenuates hypoxia-induced drug resistance. In contrast, knockdown of DUSP2 in cancer cells is sufficient to increase drug resistance. Furthermore, xenografted mice inoculated with human cancer cells demonstrate that restoration of DUSP2 expression during cancer progression significantly inhibits tumor growth and enhances drug sensitivity while loss of DUSP2 promotes tumor growth. Lastly, we found that loss of DUSP2 under normoxia causes an increase in a number of drug resistance-related genes while re-expression of DUSP2 under hypoxia decreases the expression of these genes. Taken together, our findings provide the first evidence to demonstrate that DUSP2 may serve as a master regulator downstream of HIF-1alpha to regulate tumor growth and drug resistance via multiple mechanisms. In light of these findings, DUSP2 may be a novel molecular target for cancer therapy.
Chinese Abstract 5
Chapter 1: Introduction 17
1.1. Hypoxia in solid tumors 17
1.2. The regulation of HIF-1 18
1.3. HIF-1 and Mitogen-activated protein kinase (MAPK) 19
1.4. MAPK in cancer 20
1.5. The duration, magnitude and compartmentalization of ERK activity 21
1.6. Dual specificity phosphatases (DUSPs) 23
1.6.1. DUSP in physiological processes 24
1.6.2. DUSPs in cancer 25
1.6.3. The regulation of DUSP in cancer 27
1.7. Drug resistance 29
1.7.1. Hypoxia and drug resistance 30
1.7.2. MAPK and drug resistance 32
1.7.3. DUSPs and drug resistance 34
Chapter 2: Objective and specific aims 36
Chapter 3: Materials and Methods 38
3.1. Cell culture and treatment 38
3.2. RNA extraction and Real Time PCR 38
3.3. Extraction of nuclei protein 38
3.4. Western Blotting 39
3.5. Promoter activity assays 39
3.6. Construction of expression plasmids 40
3.7. Short Interference RNA (siRNA) 40
3.8. Chromatin Immunoprecipitation (ChIP) Assay 41
3.9. Cell viability assay 42
3.10. Collection of clinical tissue samples and Immunohistochemistry 42
3.11. To setup xenograft mouse model 43
3.12. Colony formation assay 43
3.13. TUNEL assay 44
3.14. To construct gene regulatory network 44
3.15. Statistical Analysis 45
Chapter 4: Results 46
4.1. Expression of DUSP2 in cancer tissues 46
4.2. DUSP2 expression is repressed by hypoxia in most examined human cancer cell lines 47
4.3. Hypoxia-inhibited DUSP2 expression is HIF-1-dependent 48
4.4. Hypoxia stimulates prolonged ERK1/2 phosphorylation 50
4.5. Hypoxia-induced phosphorylation of ERK is mediated by downregulation of DUSP2 50
4.6. To establish a tetracycline-inducible DUSP2 system to investigate the functional role of DUSP2 in cancer progression 52
4.7. Induction of DUSP2 during cancer progression promotes cell apoptosis and tumor regression 52
4.8. Stable knockdown of DUSP2 promotes tumor growth 53
4.9. Hypoxia-induced drug resistance is mediated by activation of ERK pathway 54
4.10. Restoration of DUSP2 under hypoxia increases drug sensitivity 55
4.11. Loss of DUSP directly increases drug resistance under normoxia 56
4.12. DUSP2 negatively regulates drug resistance genes 56
Chapter 5: Discussion 58
Chapter 6: Conclusion 67
Chapter 7: References 68
Chapter 8: Figures 82
Table 1: Relation of DUSP2 expression and various prognostic factors in 102 patients with colon cancer 138
Table 2: List of primers used in this study 139
Table 3: List of siRNAs used in this study. 141
Figure 1. DUSP2 expression is significantly reduced in different kind of cancer cells. 82
Figure 2. DUSP2 antibody has a good specificity to detect endogenous and exogenous DUSP2. 83
Figure 3. DUSP2 protein is downregulated and inversely correlated with hypoxic index in cervical cancer. 84
Figure 4. The levels of DUSP2 protein is reduced in colorectal cancer and inversely correlated with stage of the disease. 85
Figure 5. Hypoxia inhibits DUSP2 expression. 86
Figure 6. PDK1 expression is used to be a positive control under hypoxia. 87
Figure 7. Hypoxia inhibits DUSP2 protein expression in cervical and colorectal cancer cell lines. 88
Figure 8. Hypoxia fails to repress DUSP2 expression in liver caner cell lines. 89
Figure 9. Hypoxia inhibits DUSP2 mRNA expression in cervical and colorectal cancer cell lines. 90
Figure 10. Hypoxia-repressed DUSP2 expression is mediated by HIF-1alpha. 91
Figure 11. Forced-expression of HIF-1alpha under normoxia directly represses DUSP2 protein expression. 92
Figure 12. Hypoxia-inhibited DUSP2 promoter activity is through the HRE in DUSP2 promoter. 93
Figure 13. HRE is conserved in mammalians. 94
Figure 14. Overexpression of HIF-1alpha under normoxia directly inhibits DUSP2 promoter in cervical cancer cell line but not in liver cancer cell line. 95
Figure 15. HIF-1alpha directly binds to predicted HRE in DUSP2 promoter region. 96
Figure 16. Hypoxia causes ERK prolonged-phosphorylation. 97
Figure 17. Hypoxia fails to stimulate phospho-p38 and phospho-JNK activation. 98
Figure 18. Forced-expression of HIF-1alpha directly decreases DUSP2 expression while increases ERK phosphorylation. 99
Figure 19. Hypoxia-induced phospho-ERK mainly accumulates in nucleus. 100
Figure 20. Hypoxia-repressed DUSP2 expression occurs at earlier time point. 101
Figure 21. Hypoxia-induced phospho-ERK occurs at later time point. 102
Figure 22. Hypoxia induces DUSP1, DUSP4 and DUSP5 expression. 103
Figure 23. Hypoxia-induced DUSP1, DUSP4 and DUSP5 expressions are ERK dependent. 104
Figure 24. Hypoxia-induced DUSP1, DUSP4 and DUSP5 expressions are DUSP2 dependent. 105
Figure 25. Substrate specificity of DUSP1 and DUSP2. 106
Figure 26. Hypoxia-induced ERK phosphorylation is mediated by downregulation of DUSP2. 107
Figure 27. Hypoxia-induced ERK phosphorylation is attenuated by overexpression of DUSP2 under hypoxia. 108
Figure 28. Induction of DUSP2-GFP reduced activity of ERK and p38 in different inducible clones. 109
Figure 29. Induction of exogenous DUSP2-GFP expresses higher level than endogenous DUSP2 expression in inducible clone. 110
Figure 30. Hypoxia-induced ERK phosphorylation is attenuated by induction of DUSP2 under hypoxia. 111
Figure 31. Hypoxia-induced ERK phosphorylation is not affected by induction of GFP under hypoxia. 112
Figure 32. Induction of DUSP2 under normoxia directly caused cell apoptosis. 113
Figure 33. Induction of DUSP2 during cancer formation inhibits tumor growth. 114
Figure 34. Induction of DUSP2 during cancer formation significantly reduces tumor weight. 115
Figure 35. Induction of DUSP2 during cancer formation causes cell apoptosis. 116
Figure 36. Induction of GFP alone during cancer formation fail to inhibit tumor growth. 117
Figure 37. Induction of GFP alone during cancer formation fails to reduce tumor weight. 118
Figure 38. HeLa cells carrying DUSP2-GFP funsion or GFP alone are still successfully induced in mice tumor model. 119
Figure 39. DUSP2 shRNA successfully and specifically knocks down endogenous DUSP2 expression. 120
Figure 40. Loss of DUSP2 expression significantly promotes tumor growth. 121
Figure 41. Dose-dependent killing of HeLa and HCT116 cells by paclitaxel, cisplatin, and oxaliplatin under normoxia. 122
Figure 42. Hypoxia causes drug resistance. 123
Figure 43. Chemical hypoxia also causes drug resistance. 124
Figure 44. Hypoxia-induced drug resistance is attenuated by blocking ERK signaling pathway. 125
Figure 45. Hypoxia-induced drug resistance is attenuated by induction of DUSP2 expression under hypoxia. 126
Figure 46. 10 mg/kg body weight of paclitaxel fails to synergistically reduce tumor growth with induction of DUSP2. 127
Figure 47. Induction of DUSP2 in xenograft tumors restores drug sensitivity of cancer cells. 128
Figure 48. Stable knockdown of DUSP2 significantly increase drug resistance under normoxia. 129
Figure 49. Stable knockdown of DUSP2 significantly increase cell number and sizes of colonies when grown in soft agar. 130
Figure 50. HIF-1α mediates gene regulatory network via regulation of DUSP2 expression. 131
Figure 51. Hypoxia increases EGR1 expression. 132
Figure 52. Hypoxia-induced EGR1 expression is through ERK signaling pathway. 133
Figure 53. DUSP2 negatively regulates EGR-1 expression. 134
Figure 54. Loss of DUSP2 expression significantly upregulates downstream target gene expressions involved in increasing drug resistance. 135
Figure 55. Induction of DUSP2 expression under hypoxia reduces downstream target gene expressions involved in increasing drug resistance. 136
Figure 56. New insight of hypoxia-induced drug resistance via downregulation of DUSP2 in cancer cells. 137
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