Furuya Hideki, Hayashi Kazukuni, Shimizu Yoshiko, Kim Nari, Tsukikawa Yutaro, Chen Runpu, Sun Yijun, Chan Owen T M, Pagano Ian, Peres Rafael, Hokutan Kanani, Igari Fumie, Chan Keith S, Rosser Charles J
Clinical & Translational Research Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, 96822, USA.
J Transl Med. 2020 Feb 5;18(1):57. doi: 10.1186/s12967-020-02239-6.
Accumulating evidence suggests that plasminogen activator inhibitor-1 (PAI-1) plays an important role in bladder tumorigenesis by regulating cell cycle. However, it remains unclear whether and how inhibition of PAI-1 suppresses bladder tumorigenesis.
To elucidate the therapeutic effect of PAI-1 inhibition, we tested its tumorigenicity in PAI-1 knockout (KO) mice exposed to a known bladder carcinogen.
PAI-1 deficiency did not inhibit carcinogen-induced bladder cancer in mice although carcinogen-exposed wild type mice significantly increased PAI-1 levels in bladder tissue, plasma and urine. We found that PAI-1 KO mice exposed to carcinogen tended to upregulate protein C inhibitor (PAI-3), urokinase-type plasminogen activator (uPA) and tissue-type PA (tPA), and significantly increased PAI-2, suggesting a potential compensatory function of these molecules when PAI-1 is abrogated. Subsequent studies employing gene expression microarray using mouse bladder tissues followed by post hoc bioinformatics analysis and validation experiments by qPCR and IHC demonstrated that SERPING1 is further downregulated in PAI-1 KO mice exposed to BBN, suggesting that SERPING1 as a potential missing factor that regulate PAI-2 overexpression (compensation pathway).
These results indicate that serpin compensation pathway, specifically PAI-2 overexpression in this model, supports bladder cancer development when oncoprotein PAI-1 is deleted. Further investigations into PAI-1 are necessary in order to identify true potential targets for bladder cancer therapy.
越来越多的证据表明，纤溶酶原激活物抑制剂-1（PAI-1）通过调节细胞周期在膀胱肿瘤发生中起重要作用。然而，PAI-1的抑制是否以及如何抑制膀胱肿瘤发生仍不清楚。
为了阐明PAI-1抑制的治疗效果，我们在暴露于已知膀胱致癌物的PAI-1基因敲除（KO）小鼠中测试了其致瘤性。
尽管暴露于致癌物的野生型小鼠膀胱组织、血浆和尿液中的PAI-1水平显著升高，但PAI-1缺乏并未抑制小鼠致癌物诱导的膀胱癌。我们发现，暴露于致癌物的PAI-1 KO小鼠倾向于上调蛋白C抑制剂（PAI-3）、尿激酶型纤溶酶原激活物（uPA）和组织型PA（tPA），并显著增加PAI-2，这表明当PAI-1缺失时，这些分子具有潜在的补偿功能。随后使用小鼠膀胱组织进行基因表达微阵列分析，随后进行事后生物信息学分析以及通过qPCR和IHC进行验证实验，结果表明，在暴露于BBN的PAI-1 KO小鼠中，SERPING1进一步下调，这表明SERPING1是调节PAI-2过表达（补偿途径）的潜在缺失因子。
这些结果表明，丝氨酸蛋白酶抑制剂补偿途径，特别是该模型中PAI-2的过表达，在癌蛋白PAI-1缺失时支持膀胱癌的发展。为了确定膀胱癌治疗的真正潜在靶点，有必要对PAI-1进行进一步研究。
