孕激素对恶性黑素瘤生长及抗炎因子表达的影响
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摘要
目的
1．研究本地区原发性皮肤黑素瘤(Cutaneous malignant melanoma，CMM)初诊时预后评估状况，性别因素与临床分期的关系。
2．研究孕激素受体(Progesterone receptor,PR)在CMM中的表达情况，以及PR表达对CMM细胞增殖、抗凋亡以及免疫表型的影响。
3．研究孕激素对黑素瘤细胞系体外生长、抗炎因子表达的影响及信号传导通路。
方法
1．收集近20年本地区所诊断、未经处理并具有完整临床、病理资料的原发性CMM43例，回顾性分析其临床、组织病理特征，进行预后评估分析。
2．以免疫组化法检测35例原发性CMM病人40份标本PR及增殖性细胞核抗原(Proliferative cell nuclear antigen，PCNA)、抗凋亡蛋白BcI-2(B-cellCLL／lymphoma 2)、免疫抑制分子人类白细胞抗原G(Human leukocyte antigen-G，HLA-G)的表达，分析PR表达与PCNA、Bcl-2、HLA-G表达及CMM临床组织学预后变量的相关性。
3．体外培养黑素瘤细胞系A375及A875，间接免疫荧光法检测黑素瘤细胞系A375及A875 PR蛋白表达。
4．以不同浓度孕激素、PR拮抗剂RU486、MEK1／2抑制剂U0126抑制以及PI3-K/Akt抑制剂LY294002对体外培养黑素瘤细胞系A375及A875进行干预。
5．MTT法检测孕激素对黑素瘤细胞体外生长的影响；流式细胞术检测孕激素对黑素细胞凋亡的影响。
6．RT-PCR、ELISA或Western blot法分别检测干预处理后黑素瘤细胞IL-10、TGF-β1及HLA-G mRNA及蛋白表达。
7．Western blot检测MAPK信号途径ERK1／2磷酸化及PI3-K／Akt信号途径Akt磷酸化水平。
结果
1．湖北地区43例原发性CMM初诊时预后评估的回顾性分析
1)湖北地区43例原发性CMM初诊时临床分期Ⅰ-Ⅱ期27例(27／43，62．8％)，Ⅲ-Ⅳ期16例(16／43，37．2％)；男女性别比2．91：1；平均年龄57．9±1．92岁；平均发病-诊断间期为1．74±0．2年；平均Breslow厚度为1．66±0．19 mm；溃疡12例(27．9％)；水平放射性生长9例(20．9％)，垂直性生长34例(79．1％)；无炎细胞浸润18．6％，低中度炎细胞浸润58％，显著炎细胞浸润23．3％。
2)临床分期与其他预后变量的关系：临床Ⅰ-Ⅱ期与Ⅲ-Ⅳ期临床组织学特征比较，性别比无明显差异(x~2=0．430,P=0．512)；高分期多见于Breslow厚度大于1．00mm肿瘤(x~2=14．149,P=0．001)及垂直生长性肿瘤(x~2=6．475,P=0．009)。
3)比较近2个10年间本地区原发性CMM的主要预后变量，发病-诊断间期缩短(2．24年与1．48年，P=0．017)，其它预后变量无显著变化。
2．CMM中PR的表达情况及意义
1)在CMM中PR的阳性表达率为25．7％，在痣细胞痣中无表达；PR在CMM与痣细胞痣中表达的差异有统计学意义(Fisher确切概率法，P＜0．01)。
2)与临床组织学预后变量的关系：女性(P=0．416)、年龄≤55岁(P=0．416)、病程＞1年(P=0．129)、溃疡(P=0．416)以及非肢端型组织亚型(P=0．416)PR阳性比例增高，但均无统计学意义。
3)与肿瘤生长的关系：PR与PCNA表达呈显著负相关(r=-0．353，P=0．026)，PR与Bcl-2表达的无相关性。
4)与免疫负调节分子HLA-G表达的关系：HLA-G与PR在黑素瘤中均有表达，但两者无显著相关性(r=0．012,P=0．946)。HLA-G表达与炎性细胞浸润有关(Fisher'sexact test，P=0．032)，与Bcl-2显著正相关(r=0．440，P=0．008)。
3．孕激素对黑素瘤细胞细胞系A375及A875体外生长的影响
1)黑素瘤细胞系A375及A875均无细胞核内PR蛋白表达。
2)孕激素对两株细胞生长均有影响，低浓度时表现为促生长效应，随浓度增高促增殖效应减弱并出现抑制效应。
3)孕激素的促生长效应可被MEK1／2抑制剂U0126抑制，但不能被PR拮抗剂RU486拮抗。
4)孕激素浓度≥1×10~(-7)M时呈剂量依赖方式促进细胞凋亡。
5)低浓度孕激素(1×10~(-9)M)上调ERK1／2磷酸化水平，高浓度(1×10~(-6)M)下调ERK1／2磷酸化水平。
4．孕激素对黑素瘤细胞抗炎分子表达的影响
1)黑素瘤细胞系A375及A875均在mRNA及蛋白水平表达IL-10及TGF-β1。
2)孕激素浓度≥1×10~(-7)M对两株细胞IL-10表达均有显著上调作用；孕激素对TGF-β1表达无明显影响；孕激素不能诱导HLA-G表达。
3)Akt抑制剂LN294002可消除孕激素对IL-10表达上调效应，但RU486无拮抗效应。
4)孕激素浓度为1×10~(-7)M时上调A375细胞Akt磷酸化水平。
结论
1．本地区原发性CMM男性发病高于女性，初诊时临床分期偏高，与临床高分期有关的预后变量为肿瘤Breslow厚度及垂直生长模式。
2．本组部分病例表达PR，并与恶性转化、肿瘤生长相关。
3．低浓度孕激素刺激黑素瘤细胞细胞系A375及A875体外生长，而高浓度孕激素抑制黑素瘤细胞体外生长；孕激素对黑素瘤生长调节效应不依赖经典核PR；孕激素对黑素瘤生长调节效应与MPAK信号通路活化有关。
4．黑素瘤细胞细胞系A375及A875均在mRNA及蛋白水平表达IL-10及TGF-β1；孕激素可呈剂量依赖方式上调IL-10表达，并与PI3-K/Akt信号通路活化有关；孕激素对黑素瘤细胞IL-10的调节效应不依赖经典核PR。
Objective
1.To evaluate the prognoses of newly diagnosed primary cutaneous malignant melanoma(CMM) in Hubai area,including relationship between clinical stage and gender.
2.To study progesterone receptors (PR) expression in primary CMM,and PR effects onmalignant melanoma growth,malignant transformation and immune inhibitoryphenotype.
3.To study progesterone effects on malignant melanoma cell lines growth,apoptosis,theexpression regulation of anti-inflammatory molecules (immunosuppressive moleculesIL-10,TGF-β1 and HLA-G),and the signaling pathway related to it in vitro.
Methods
1.Among patients with primary CMM recorded in the area in the last 20 years,acollection of complete clinical and pathological data was reviewed,and the prognoseswere assessed.
2.PR,proliferative cell nuclear antigen (PCNA),Bcl-2 and human leukocyte antigen -G(HLA-G) expression in a series of 40 specimens from 35 patients with CMM wereevaluated by immunohistochemistry,and the correlations between theimmunohistochemistry findings and clinicohistopathology date were also analyzed.
3.PR protein expression was identified by Indirect Immunofluorescence Assay in culturedmalignant melanoma cell lines A375 and A875 in vitro.
4.Cultured malignant melanoma cell lines A375 and A875 were treated with a serialconcentration of progesterone,its antagonist RU486,MEK1/2inhibitor U0126 or AKtinhibitor LY294002.
5.MTT assay was employed to determine the growth regulatory effects of progesterone,and Flow Cytometry Analysis was used to determine apoptosis rate.
6.The level of IL-10、TGF-β1 and HLA-G mRNA and protein expression weredetermined by RT-PCR and ELISA or Western blot Assay.
7.Activated MPAK,PI3K/Akt pathway was evaluated by the level of ERK1/2 and Aktphosphorylation,respectively,with Western blot Assay.
Results
1.The prognosis assessments of primary cutaneous malignant melanoma in Hubai area.
1) Among 43 cases newly diagnosed primary CMM in Hubai area,27 (62.8%)wereclinical stageⅠ-Ⅱtumors and 16 (37.2%) stageⅢ-Ⅳ,sex ratio F/M 2.91:1,the meanage 57.9±1.92 years old,the mean diagnosis delay 1.74±0.2 years,mean Breslowthickness 1.66±0.19mm,ulceration 27.9%,radial growth pattern 20.9% and verticalgrowth pattern 79.1%,non-brisk inflammatory infiltrate 58% and brisk 23.3%.
2) The relation between clinical staging and other prognostic variables:no significantdeference of clinical staging was observed between males and females (x~2=0.430,P=0.512),advanced clinical stage was significantly correlated with Breslow thicknessmore than 1mm (x~2=14.149,P=0.001),and tumors with vertical growth pattern(x~2=6.475,P= 0.009) .
3) In last two decades,there were significant shorter delay in diagnosis in the second10-years than in the first (p=0.017),and no significant differences of other variables.
2.Expression and the role of progesterone receptor in primary CMM
1) PR expression was detected in 25.7% (9/35) of CMM,no PR expression was observedin nevi,the difference is significant (Fisher's exact tests,P＜0.01 ) .
2) There is a slight increasing of PR expression in female,aged less than 55 years,diagnosis delay longer than 1 years,ulceration and non-acral histopathology subtype,but not reaching statistic significance(P=0.416,0.416,0.129,0.416,0.416,respectively).
3) PR expression was significantly inversely correlated with PCNA expression(r=0.012,P=0.946),and not with Bcl-2.
4) PR and immunosuppressive molecule human leukocyte antigen-G were detected insome cases,but significant correlation was not obtained (r=0.012,P=0.946),HLA-Gexpression was significantly correlated with Bcl-2(r=0.440,P=0.008).
3.The effects of progesterone on growth regulation in malignant melanoma cells linesA375 and A875 in vitro.
1) Both A375 and A875 are progesterone receptor-negative.
2) Lower concentration progesterone enhanced both two cell lines proliferation,but thisgrowth regulation effect reversed when incubated with 1×10~(-7)M and higherconcentration progesterone.
3) The growth regulatory effect can be inhibited by MAPK inhibitor U0126,but can notbe abolished by progesterone antagonist RU486.
4) High concentration (≥1×10~(-7)M) progesterone promoted A375 and A875 apoptosis in adose-dependented manner.
5) The level of ERK1/2 phosphorylation increased by lower concentration (1×10~(-9)M)progesterone,but reduced by high concentration (1×10~(-6)M) progesterone.
4.Progesterone effects on immune inhibitory ligands expression in melanoma cells invitro.
1 ) TGF-β1 and IL-10 mRNA and protein can be detected in both A375 and A875 cellsunder serum-free culture conditions as measured by RT-PCR and ELISA.
2) High concentration progesterone(≥1×10~(-7)M) enhanced IL-10 expression both in A375and A875 cells,but did not alter TGF-β1 expression,and not induce HLA-Gexpression.
3) LY294002 abrogated progesterone effects on IL-10 expression regulation,but not progesterone antagonist RU486.
4) High concentration progesterone(≥1×10~(-7)M) increased the level of Aktphosphoryiation in A375 cells.
Conclusions
1.The newly diagnosis cutaneous primary malignant melanoma in this area had apredilection for males,and were more likely to have advanced stages of disease atpresentation.Advanced clinical stage was associated with Breslow thickness andvertical growth pattern.
2.Progesterone receptors expressed in some of primary cutaneous malignant melanoma,and PR expression associated with tumor growth and malignant transformation.
3.Progesterone exhibit growth regulation on malignant melanoma cell throughnon-genomic mechanism.
4.Progesterone stimulates PI3K-dependent signal pathway leading to the up-regulation ofIL-10 gene expression in melanoma cells.
1．研究本地区原发性皮肤黑素瘤(Cutaneous malignant melanoma，CMM)初诊时预后评估状况，性别因素与临床分期的关系。
2．研究孕激素受体(Progesterone receptor,PR)在CMM中的表达情况，以及PR表达对CMM细胞增殖、抗凋亡以及免疫表型的影响。
3．研究孕激素对黑素瘤细胞系体外生长、抗炎因子表达的影响及信号传导通路。
方法
1．收集近20年本地区所诊断、未经处理并具有完整临床、病理资料的原发性CMM43例，回顾性分析其临床、组织病理特征，进行预后评估分析。
2．以免疫组化法检测35例原发性CMM病人40份标本PR及增殖性细胞核抗原(Proliferative cell nuclear antigen，PCNA)、抗凋亡蛋白BcI-2(B-cellCLL／lymphoma 2)、免疫抑制分子人类白细胞抗原G(Human leukocyte antigen-G，HLA-G)的表达，分析PR表达与PCNA、Bcl-2、HLA-G表达及CMM临床组织学预后变量的相关性。
3．体外培养黑素瘤细胞系A375及A875，间接免疫荧光法检测黑素瘤细胞系A375及A875 PR蛋白表达。
4．以不同浓度孕激素、PR拮抗剂RU486、MEK1／2抑制剂U0126抑制以及PI3-K/Akt抑制剂LY294002对体外培养黑素瘤细胞系A375及A875进行干预。
5．MTT法检测孕激素对黑素瘤细胞体外生长的影响；流式细胞术检测孕激素对黑素细胞凋亡的影响。
6．RT-PCR、ELISA或Western blot法分别检测干预处理后黑素瘤细胞IL-10、TGF-β1及HLA-G mRNA及蛋白表达。
7．Western blot检测MAPK信号途径ERK1／2磷酸化及PI3-K／Akt信号途径Akt磷酸化水平。
结果
1．湖北地区43例原发性CMM初诊时预后评估的回顾性分析
1)湖北地区43例原发性CMM初诊时临床分期Ⅰ-Ⅱ期27例(27／43，62．8％)，Ⅲ-Ⅳ期16例(16／43，37．2％)；男女性别比2．91：1；平均年龄57．9±1．92岁；平均发病-诊断间期为1．74±0．2年；平均Breslow厚度为1．66±0．19 mm；溃疡12例(27．9％)；水平放射性生长9例(20．9％)，垂直性生长34例(79．1％)；无炎细胞浸润18．6％，低中度炎细胞浸润58％，显著炎细胞浸润23．3％。
2)临床分期与其他预后变量的关系：临床Ⅰ-Ⅱ期与Ⅲ-Ⅳ期临床组织学特征比较，性别比无明显差异(x~2=0．430,P=0．512)；高分期多见于Breslow厚度大于1．00mm肿瘤(x~2=14．149,P=0．001)及垂直生长性肿瘤(x~2=6．475,P=0．009)。
3)比较近2个10年间本地区原发性CMM的主要预后变量，发病-诊断间期缩短(2．24年与1．48年，P=0．017)，其它预后变量无显著变化。
2．CMM中PR的表达情况及意义
1)在CMM中PR的阳性表达率为25．7％，在痣细胞痣中无表达；PR在CMM与痣细胞痣中表达的差异有统计学意义(Fisher确切概率法，P＜0．01)。
2)与临床组织学预后变量的关系：女性(P=0．416)、年龄≤55岁(P=0．416)、病程＞1年(P=0．129)、溃疡(P=0．416)以及非肢端型组织亚型(P=0．416)PR阳性比例增高，但均无统计学意义。
3)与肿瘤生长的关系：PR与PCNA表达呈显著负相关(r=-0．353，P=0．026)，PR与Bcl-2表达的无相关性。
4)与免疫负调节分子HLA-G表达的关系：HLA-G与PR在黑素瘤中均有表达，但两者无显著相关性(r=0．012,P=0．946)。HLA-G表达与炎性细胞浸润有关(Fisher'sexact test，P=0．032)，与Bcl-2显著正相关(r=0．440，P=0．008)。
3．孕激素对黑素瘤细胞细胞系A375及A875体外生长的影响
1)黑素瘤细胞系A375及A875均无细胞核内PR蛋白表达。
2)孕激素对两株细胞生长均有影响，低浓度时表现为促生长效应，随浓度增高促增殖效应减弱并出现抑制效应。
3)孕激素的促生长效应可被MEK1／2抑制剂U0126抑制，但不能被PR拮抗剂RU486拮抗。
4)孕激素浓度≥1×10~(-7)M时呈剂量依赖方式促进细胞凋亡。
5)低浓度孕激素(1×10~(-9)M)上调ERK1／2磷酸化水平，高浓度(1×10~(-6)M)下调ERK1／2磷酸化水平。
4．孕激素对黑素瘤细胞抗炎分子表达的影响
1)黑素瘤细胞系A375及A875均在mRNA及蛋白水平表达IL-10及TGF-β1。
2)孕激素浓度≥1×10~(-7)M对两株细胞IL-10表达均有显著上调作用；孕激素对TGF-β1表达无明显影响；孕激素不能诱导HLA-G表达。
3)Akt抑制剂LN294002可消除孕激素对IL-10表达上调效应，但RU486无拮抗效应。
4)孕激素浓度为1×10~(-7)M时上调A375细胞Akt磷酸化水平。
结论
1．本地区原发性CMM男性发病高于女性，初诊时临床分期偏高，与临床高分期有关的预后变量为肿瘤Breslow厚度及垂直生长模式。
2．本组部分病例表达PR，并与恶性转化、肿瘤生长相关。
3．低浓度孕激素刺激黑素瘤细胞细胞系A375及A875体外生长，而高浓度孕激素抑制黑素瘤细胞体外生长；孕激素对黑素瘤生长调节效应不依赖经典核PR；孕激素对黑素瘤生长调节效应与MPAK信号通路活化有关。
4．黑素瘤细胞细胞系A375及A875均在mRNA及蛋白水平表达IL-10及TGF-β1；孕激素可呈剂量依赖方式上调IL-10表达，并与PI3-K/Akt信号通路活化有关；孕激素对黑素瘤细胞IL-10的调节效应不依赖经典核PR。
Objective
1.To evaluate the prognoses of newly diagnosed primary cutaneous malignant melanoma(CMM) in Hubai area,including relationship between clinical stage and gender.
2.To study progesterone receptors (PR) expression in primary CMM,and PR effects onmalignant melanoma growth,malignant transformation and immune inhibitoryphenotype.
3.To study progesterone effects on malignant melanoma cell lines growth,apoptosis,theexpression regulation of anti-inflammatory molecules (immunosuppressive moleculesIL-10,TGF-β1 and HLA-G),and the signaling pathway related to it in vitro.
Methods
1.Among patients with primary CMM recorded in the area in the last 20 years,acollection of complete clinical and pathological data was reviewed,and the prognoseswere assessed.
2.PR,proliferative cell nuclear antigen (PCNA),Bcl-2 and human leukocyte antigen -G(HLA-G) expression in a series of 40 specimens from 35 patients with CMM wereevaluated by immunohistochemistry,and the correlations between theimmunohistochemistry findings and clinicohistopathology date were also analyzed.
3.PR protein expression was identified by Indirect Immunofluorescence Assay in culturedmalignant melanoma cell lines A375 and A875 in vitro.
4.Cultured malignant melanoma cell lines A375 and A875 were treated with a serialconcentration of progesterone,its antagonist RU486,MEK1/2inhibitor U0126 or AKtinhibitor LY294002.
5.MTT assay was employed to determine the growth regulatory effects of progesterone,and Flow Cytometry Analysis was used to determine apoptosis rate.
6.The level of IL-10、TGF-β1 and HLA-G mRNA and protein expression weredetermined by RT-PCR and ELISA or Western blot Assay.
7.Activated MPAK,PI3K/Akt pathway was evaluated by the level of ERK1/2 and Aktphosphorylation,respectively,with Western blot Assay.
Results
1.The prognosis assessments of primary cutaneous malignant melanoma in Hubai area.
1) Among 43 cases newly diagnosed primary CMM in Hubai area,27 (62.8%)wereclinical stageⅠ-Ⅱtumors and 16 (37.2%) stageⅢ-Ⅳ,sex ratio F/M 2.91:1,the meanage 57.9±1.92 years old,the mean diagnosis delay 1.74±0.2 years,mean Breslowthickness 1.66±0.19mm,ulceration 27.9%,radial growth pattern 20.9% and verticalgrowth pattern 79.1%,non-brisk inflammatory infiltrate 58% and brisk 23.3%.
2) The relation between clinical staging and other prognostic variables:no significantdeference of clinical staging was observed between males and females (x~2=0.430,P=0.512),advanced clinical stage was significantly correlated with Breslow thicknessmore than 1mm (x~2=14.149,P=0.001),and tumors with vertical growth pattern(x~2=6.475,P= 0.009) .
3) In last two decades,there were significant shorter delay in diagnosis in the second10-years than in the first (p=0.017),and no significant differences of other variables.
2.Expression and the role of progesterone receptor in primary CMM
1) PR expression was detected in 25.7% (9/35) of CMM,no PR expression was observedin nevi,the difference is significant (Fisher's exact tests,P＜0.01 ) .
2) There is a slight increasing of PR expression in female,aged less than 55 years,diagnosis delay longer than 1 years,ulceration and non-acral histopathology subtype,but not reaching statistic significance(P=0.416,0.416,0.129,0.416,0.416,respectively).
3) PR expression was significantly inversely correlated with PCNA expression(r=0.012,P=0.946),and not with Bcl-2.
4) PR and immunosuppressive molecule human leukocyte antigen-G were detected insome cases,but significant correlation was not obtained (r=0.012,P=0.946),HLA-Gexpression was significantly correlated with Bcl-2(r=0.440,P=0.008).
3.The effects of progesterone on growth regulation in malignant melanoma cells linesA375 and A875 in vitro.
1) Both A375 and A875 are progesterone receptor-negative.
2) Lower concentration progesterone enhanced both two cell lines proliferation,but thisgrowth regulation effect reversed when incubated with 1×10~(-7)M and higherconcentration progesterone.
3) The growth regulatory effect can be inhibited by MAPK inhibitor U0126,but can notbe abolished by progesterone antagonist RU486.
4) High concentration (≥1×10~(-7)M) progesterone promoted A375 and A875 apoptosis in adose-dependented manner.
5) The level of ERK1/2 phosphorylation increased by lower concentration (1×10~(-9)M)progesterone,but reduced by high concentration (1×10~(-6)M) progesterone.
4.Progesterone effects on immune inhibitory ligands expression in melanoma cells invitro.
1 ) TGF-β1 and IL-10 mRNA and protein can be detected in both A375 and A875 cellsunder serum-free culture conditions as measured by RT-PCR and ELISA.
2) High concentration progesterone(≥1×10~(-7)M) enhanced IL-10 expression both in A375and A875 cells,but did not alter TGF-β1 expression,and not induce HLA-Gexpression.
3) LY294002 abrogated progesterone effects on IL-10 expression regulation,but not progesterone antagonist RU486.
4) High concentration progesterone(≥1×10~(-7)M) increased the level of Aktphosphoryiation in A375 cells.
Conclusions
1.The newly diagnosis cutaneous primary malignant melanoma in this area had apredilection for males,and were more likely to have advanced stages of disease atpresentation.Advanced clinical stage was associated with Breslow thickness andvertical growth pattern.
2.Progesterone receptors expressed in some of primary cutaneous malignant melanoma,and PR expression associated with tumor growth and malignant transformation.
3.Progesterone exhibit growth regulation on malignant melanoma cell throughnon-genomic mechanism.
4.Progesterone stimulates PI3K-dependent signal pathway leading to the up-regulation ofIL-10 gene expression in melanoma cells.
引文
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