肝癌在台灣有很高的發生率，在2015年的統計肝癌位居國人癌症的第四位。肝癌發生在男性比女性高約兩倍到四倍，因此賀爾蒙及其接受器可能與肝癌應有密切的關係，在過去的研究發現肝癌細胞可以有雄激素受器(androgen receptor)及雌激素受器(estrogen receptor)的表達，雄激素受器可能有促進肝癌形成的作用，而雌激素受器則可能有抑制肝癌形成的作用。有趣的是，研究發現肝炎病毒蛋白可能與這些荷爾蒙接受器會有交互作用，暗示荷爾蒙及其接受器所調控的訊息傳遞路徑，對肝癌的發生可能扮演重要的角色。我們過去在蛋白質質體分析中，利用SDS-PAGE分離蛋白質，配合串聯質譜儀的定序分析。我們發現了一個與荷爾蒙相關的受器蛋白: 孕酮受體膜蛋白單元1 (progesterone receptor membrane component 1, PGRMC1)。因此本研究我們探討了PGRMC1及其膜接合孕酮受質蛋白(membrane-associated progesterone receptor)家族成員PGRMC2在肝癌的表現，與肝癌的臨床病理參數（包括分化、侵犯和轉移等）、復發或存活率之相關性，以期對臨床病患預後的預測，和發展新的肝癌治療方向有所幫助。
本研究分析了成大89個肝癌檢體及其配對的非腫瘤肝臟組織檢體，我們進行了雌激素受體（ER），孕激素受體（PR），PGRMC1和PGRMC2的免疫組織化學染色。我們還利用The Cancer Genome Atlas（TCGA）的肝癌數據，其包含了373個肝癌檢體，來分析PGRMC1和PGRMC2的表現。我們也在肝癌細胞株中，評估PGRMC1對細胞增殖，分化，移動和侵襲的影響。分析顯示，肝癌組織很少表達ER（5.6％）和PR（4.5％）。相對的，大多數肝癌組織會表達PGRMC1（89.9％）和PGRMC2（100％）。PGRMC1與PGRMC2在肝癌組織表現較非腫瘤肝組織為低。肝癌中PGRMC1表達降低與較高的血清甲胎蛋白(alpha-fetoprotein)（P = 0.004），較差的腫瘤分化（P = 0.045）和較多的腫瘤肝臟包膜(liver capsule)穿透（P = 0.038）有顯著相關。PGRMC1與肝癌復發有顯著相關性。在多變異分析中，低PGRMC1表達是為腫瘤復發之獨立因子(P=0.002, HR=2.384, CI=1.377-4.128)，而在TCGA的肝癌數據分析，低PGRMC1表達是為腫瘤復發(P<0.001, HR=2.857, CI=1.781-4.584)及較差的術後總存活(P=0.020, HR=1.556, CI=1.072-2.260)之獨立因子，而PGRMC2與肝癌復發無顯著相關性。我們在細胞株的實驗中，發現PGRMC1 knockdown會造成腫瘤細胞分化變差及細胞的增殖變快，而PGRMC1過度表達則引起相反的作用。因此PGRMC1在肝癌發生扮演重要角色，並且其表達下降可當成是一個不良預後的指標，針對PGRMC1的標靶治療或賀爾蒙治療可能是發展肝癌治療的一個新方向。

Hepatocellular carcinoma (HCC) is a sexually dimorphic disease with a significantly higher incidence in males than females. However, the role of hormonal receptors in HCC remains unclear. This study was designed to examine the significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in HCC.
We performed immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n=373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.
We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P<0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P=0.004), poorer tumor differentiation (P=0.045) and liver capsule penetration (P=0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P=0.002, HR=2.384, CI=1.377-4.128) in our cases, as well as in the TCGA cohort (P<0.001, HR=2.857, CI=1.781-4.584). Expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted poorly differentiated phenotype and proliferation of HCC cells in vitro while PGRMC1 overexpression caused the opposite effects.
In conclusion, PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.

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