The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer.
The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer.
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DOI：
10.1186/s10020-018-0035-4
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发表时间：
2018-06-27
期刊：
影响因子：
--
通讯作者：
Persson JL
中科院分区：
文献类型：
--
作者：
Mandel A;Larsson P;Sarwar M;Semenas J;Syed Khaja AS;Persson JL
转移性前列腺癌(PCa)细胞已获得生存和侵袭优势。表皮生长因子(EGF)受体是一种受体酪氨酸激酶，可能介导促进多种癌症进展和侵袭的信号转导。在这项研究中，我们揭示了雄激素受体(AR)、基质金属蛋白酶-9(MMP9)和EGFR之间相互联系促进PCa进展的分子机制。对原发和转移性前列腺癌组织芯片进行免疫组织化学分析。使用MSKCC前列腺癌基因组计划数据集(原发癌n = 181；转移癌n = 37)和癌症基因组图谱前列腺癌临时数据集(n = 495)的三个队列，分析了EGFR的临床重要性及其与生存的关系。将靶向过表达或抑制目的蛋白导入PCa细胞系。用该化合物处理前列腺癌细胞系。进行免疫印迹分析。我们认为AR、MMP9和EGFR是相互联系的因子，它们可能协同促进PCa的进展。在PCa患者中，EGFR表达的改变与较差的无病生存率有关。在雄激素刺激下，AR过表达导致前列腺癌细胞株EGFR、p-GSK-3β表达增加，p27表达降低。MMP9过表达可显著诱导PCa细胞中EGFR的表达。抑制PIP5K1α，一种作用于PI3K/AKT上游的脂激酶，可显著降低AR、MMP9和EGFR3的表达。我们的发现还表明，在雄激素依赖和去势抵抗的条件下，前列腺癌细胞可能利用AR、EGFR和MMP-9途径。我们的数据提示了一种新的治疗潜力，通过靶向前列腺癌患者亚群中的AR、EGFR和MMP-9通路来阻止癌症转移。
Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGF) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression. Immunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n = 181; for metastatic tumors n = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset (n = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed. We showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-3β and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1α, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR. Our findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.
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DOI：
10.1007/s12032-017-0918-1
发表时间：
2017-04
期刊：
Medical oncology (Northwood, London, England)
影响因子：
--
作者：
Blaszczak W;Barczak W;Wegner A;Golusinski W;Suchorska WM
通讯作者：
Suchorska WM
前列腺癌的基因表达谱揭示了多个分子途径在转移过程中的参与。
影响因子：
3.8
作者：
Chandran, Uma R.;Ma, Changqing;Dhir, Rajiv;Bisceglia, Michelle;Lyons-Weiler, Maureen;Liang, Wenjing;Michalopoulos, George;Becich, Michael;Monzon, Federico A.
通讯作者：
Monzon, Federico A.
影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
11.2
作者：
Eberlein CA;Stetson D;Markovets AA;Al-Kadhimi KJ;Lai Z;Fisher PR;Meador CB;Spitzler P;Ichihara E;Ross SJ;Ahdesmaki MJ;Ahmed A;Ratcliffe LE;O'Brien EL;Barnes CH;Brown H;Smith PD;Dry JR;Beran G;Thress KS;Dougherty B;Pao W;Cross DA
通讯作者：
Cross DA
影响因子：
82.9
作者：
Craft, N;Shostak, Y;Sawyers, CL
通讯作者：
Sawyers, CL