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研究生：	蔡昆澔 Tsai, Kun-Hao
論文名稱：	PGRMC1在肝癌中對缺氧壓力以及抗藥性的重要性 The significance of PGRMC1 on hypoxic stress and drug resistance in hepatocellular carcinoma
指導教授：	周楠華 Chow, Nan-Haw
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2022
畢業學年度：	110
語文別：	英文
論文頁數：	88
中文關鍵詞：	肝細胞癌、黃體酮受體膜組件一、經導管藥物栓塞治療法、缺氧誘導因子-1α 、表皮生長因子受體
外文關鍵詞：	Hepatocellular carcinoma, Progesterone receptor membrane component 1, Trans-arterial chemoembolization, Hypoxia-inducible factor 1α, Epidermal growth factor receptor
相關次數：	點閱：57 下載：0
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肝細胞癌(Hepatocellular carcinoma, HCC) 是國內常見十大癌症之一，經導管藥物栓塞治療法(Trans-arterial chemoembolization, TACE)被廣泛的應用在不適合進行經皮射頻燒灼、手術切除或是移植的肝癌病患中。然而，預測經導管藥物栓塞治療法預後的生物標記仍需待釐清。黃體酮受體膜組件一 (PGRMC1) 是黃體酮受體家族(membrane associated progesterone receptor, MAPR) 相關成員之一，而PGRMC1 過去被歸類於非典型的黃體酮受體。PGRMC1 可以透過與血紅素(Heme)形成雙體(dimer)，而血紅素誘導的PGRMC1 雙體可以與細胞色素P450 (cytochrome P450)以及表皮生長因子受體(EGFR) 產生交互作用。PGRMC1 在乳癌病患中的過度表達會降低病患的無病存活率(disease-free survival)，而且也會增加可增強體外細胞增殖 (cell proliferation)以及增加化療藥物的抗藥性。過去研究中指出PGRMC1 會在缺氧壞死的乳癌細胞周圍的存活組織中大量表達，我們推測PGRMC1在缺氧癌細胞組織中扮演著重要角色。我們的研究，發現肝癌細胞株中的PGRMC1表達降低，可以減緩缺氧環境下的體外細胞生長 (cell growth)。腫瘤球形成實驗發現，肝癌細胞的PGRMC1表現量，和癌症幹細胞的功能呈正向關係。PGRMC1 可以刺激EGFR磷酸化，來增加下游基因的表達，進而提升肝癌細胞株在缺氧環境的存活率。此外，PGRMC1可以透過活化EGFR，來增加缺氧誘導因子-1α(HIF-1α)的表達。相反，肝癌細胞株預先給予EGFR抑制劑得舒緩(Erlotinib)後，可以有效逆轉PGRMC1在缺氧環境下誘導的HIF-1α蛋白表達。綜合以上結果，本研究釐清肝癌細胞中缺氧環境下，PGRMC1 調控EGFR的分子機轉，也許可以應用來改善TACE對於肝癌之療效。

Hepatocellular carcinoma (HCC) is one of the top ten important cancers in Taiwan. Currently, trans-arterial chemoembolization (TACE) is widely applied in the treatment of HCC patients who are not candidates for percutaneous ablation, liver resection, or transplantation. However, biomarkers in predicting the clinical outcome after TACE remain controversial. Progesterone receptor membrane component 1(PGRMC1), one of the membrane associated progesterone receptor (MAPR) family members, has been thought as putative progesterone receptor. PGRMC1 can form as a homodimer induced by heme, and heme–mediated PGRMC1 dimerization is required for cytochrome P450 and EGFR interaction with PGRMC1. Overexpression of PGRMC1 is associated with poor disease-free survival of breast cancer patients and induces cell proliferation and chemotherapeutic resistance in vitro. Since PGRMC1 expression was localized at hypoxic zone surrounding necrotic breast cancer tissue, we hypothesized that PGRMC1 may play a role in the response of cancer cells to hypoxia. Knocking down of PGRMC1 suppressed the proliferation of HCC cells in vitro under hypoxia. HCC cells having high expression of PGRMC1 had a higher efficiency of tumor sphere formation under hypoxia compared with those with lower PGRMC1 expression. PGRMC1 stimulated EGFR phosphorylation with activation of downstream pathway, resulting in enhanced survival of HCC in vitro under hypoxia. In contrast, pretreatment with EGFR inhibitor-Erlotinib successfully reversed the PGRMC1 induced HIF-1α expression under hypoxia. PGRMC1 up-regulated the HIF-1α expression through EGFR activation. Together, PGRMC1 could enhance the survival of HCC in vitro under hypoxia through EGFR activation and HIF-1α accumulation. Clarification of mechanisms underlying interaction of PGRMC1 with EGFR in the response of HCC to hypoxic stress may improve the efficacy of TACE treatment to HCC.

Chinese Abstract	II
Abstract	III
Acknowledgment	V
Table of Contents	VI
ABBREVIATIONS	XI
Chapter1. Introduction	1
1.	Hepatocellular carcinoma	1
2.	Trans-arterial chemoembolization in HCC	2
3.	Hypoxia inducible factor-1	3
4.	Progesterone receptor membrane component 1(PGRMC1)	4
5.	Epidermal Growth Factor Receptor (EGFR)	5
6.	Drug resistance in HCC under hypoxia	6
Chapter 2. Materials and Methods	7
1.	Cell culture, cell lines and hypoxia chamber	7
2.	Knockdown and overexpression of PGRMC1	7
3.	Western blotting	8
4.	Cell proliferation assay	9
5.	Immunoprecipitation	9
6.	Reverse transcription-polymerase chain reaction (RT-PCR)	9
7.	Wound-healing assay	10
8.	Transwell migration assay	10
9.	Tumor-sphere formation assay	11
10.	Statistical analysis	11
Chapter3. Results	12
Part I. The biological effect of PGRMC1 on HCC under hypoxia	12
1.	Establishment of PGRMC1 stably knockdown and overexpressed cell lines	12
2.	PGRMC1 promotes cell proliferation under hypoxia in vitro.	12
3.	Effect of HIF-1α expression under Cobalt chloride (CoCl2) hypoxia mimic treatment in vitro.	13
Part II. The biological effect of PGRMC1 on HCC under hypoxia	13
4.	Expression and phosphorylation level of EGFR modulated by PGRMC1 in vitro.	13
5.	PGRMC1 in the modulation of EGFR activation by EGF in vitro.	13
6.	Effects of PGRMC1 on EGFR mRNA expression in HCC in vitro	2
7.	Interaction of PGRMC1 with EGFR in HepG2, Hep3B and PLC/PRF/5 cells in vitro.	2
8.	The effects of PGRMC1 on Caveolin-1 expression under hypoxia in vitro.	3
9.	Interaction of Caveolin-1 with EGFR in Hep3B and PLC/PRF/5 cells in vitro.	3
10.	The impact of PGRMC1 on chemosensitivity of HCC cells to Erlotinib in vitro	3
11.	Modulation of HIF-1α expression by EGFR in vitro	4
Part III. The potential signaling pathway modulate by PGRMC1 in HCC cell lines under hypoxia	4
12.	EGFR signaling pathway modulated by PGRMC1 in HCC under hypoxia	4
13.	JAK/STAT signaling pathway modulated by PGRMC1 in HCC under hypoxia	5
14.	The effect of progesterone and heme treatment in HCC cell lines.	5
15.	Overexpression of PGRMC1 in Hep-3B cells inhibit wound healing in vitro.	6
16.	The impact of PGRMC1 on tumor-sphere formation in vitro	6
Chapter4. Discussion	7
Chapter5. Conclusion	12
Chapter 6. References	13
Chapter 7. Figure legends	26
Figure 1. PGRMC1 expression in stable clones established from Hep3B, HepG2 and PLC/PRF/5 cells.	26
Figure 2. The effects of PGRMC1 on cell proliferation under hypoxia of Hep3B, HepG2 and PLC/PRF/5 cells in vitro.	28
Figure 3. The effects of PGRMC1 on HIF-1α expression under Cocl2 hypoxia mimic treatment in vitro.	30
Figure 4. Phosphorylation level of EGFR is modulated by PGRMC1 in Hep3B, HepG2 and PLC/PRF/5 cells under hypoxia in vitro.	32
Figure 5. Activation of EGFR by EGF in Hep-G2 cells is regulated by PGRMC1 in vitro	33
Figure 6. Effects of PGRMC1 on EGFR mRNA expression in Hep-3B and Hep-G2 cells in vitro.	34
Figure 7. Interaction of PGRMC1 with EGFR in HepG2 PLC/PRF/5 and Hep3B cells in vitro.	36
Figure 8. The effects of PGRMC1 on Caveolin-1 expression under hypoxia in vitro.	38
Figure 9. Interaction of Caveolin-1 with EGFR in Hep3B and PLC/PRF/5 cells in vitro.	40
Figure 10. The effects of PGRMC1 targeting on chemosensitivity to Erlotinib in vitro under hypoxia.	42
Figure 11. PGRMC1 can affect HIF-1α protein expression by modulate EGFR activity.	46
Figure 12. EGFR signaling pathway activated by PGRMC1 under hypoxia in vitro.	48
Figure 13. Jak-Stat signaling pathway activated by PGRMC1 under hypoxia in vitro.	52
Figure 14. The effects of heme on cell proliferation under hypoxia of HepG2 cells in vitro.	54
Figure 15. The effects of PGRMC1 on migration of Hep-3B cells measured by wound healing assay under hypoxia.	56
Figure 16. The impact of PGRMC1 on tumor-sphere formation in vitro	59
Figure 17. Hypothetical model for PGRMC1 in the protection of hepatocellular carcinoma under hypoxia through activation of EGFR and Jak2.	60
Chapter 8. Appendix	61
Appendix 1. EGFR signaling pathway activated by PGRMC1 under Cocl2 hypoxia mimic treatment in vitro.	64
Appendix 2. Jak-Stat signaling pathway activated by PGRMC1 under Cocl2 hypoxia mimic treatment in vitro.	68
Appendix 3. The effects of PGRMC1 targeting on chemosensitivity to chemotherapy drugs in vitro under hypoxia.	70
Appendix 4. The effects of PGRMC1 targeting on chemosensitivity to HCC first-line and second-line TKI drugs in vitro under hypoxia.	72
Appendix 5. The effects of PGRMC1 on cell proliferation and drug resistance under hypoxia of Mahlavu cells in vitro.	74
Appendix 6. The effects of PGRMC1 on transwell cell migration assay under hypoxia in vitro.	75
Appendix Table 1. The primers utilized in current study	76
                                    

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