Zaheer Javeria, Shanmugiah Joycie, Kim Seungyoun, Kim Hyeongi, Kim Jin Su
Division of Applied RI, Korea Institute of Radiological and Medical Sciences, 75 Nowon-Ro, Nowon-Gu, Seoul, 01812, Republic of Korea.
Radiological and Medical Sciences, University of Science and Technology (UST), Seoul, 01812, Republic of Korea.
Sci Rep. 2025 May 12;15(1):16449. doi: 10.1038/s41598-025-97983-4.
An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with Cu-trastuzumab (Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.
在使用铜标记曲妥珠单抗（Cu-TRZ）进行放射免疫治疗（RIT）时，胃癌中升高的细胞外基质（ECM）和间质液压力（IFP）会限制对HER2表达细胞的靶向作用。在此，我们使用氯沙坦（LOS）来下调胃癌小鼠模型中的ECM和IFP。在我们的研究中，我们用40mg/kg剂量的LOS处理胃癌小鼠模型。我们发现LOS处理使Alexa-647-TRZ的积累增加了两倍，这显著增强了Cu-TRZ。我们确定LOS处理的样本中，与ECM降解相关的基因SERPINE1的mRNA和蛋白质表达降低。此外，LOS处理导致参与ECM沉积的基因TGF-β1和COL13A1的mRNA表达下调，以及与ECM降解相关的基因MMP2的RNA表达上调。N-钙黏蛋白和E-钙黏蛋白的转移标志物没有显著变化。此外，我们的研究表明，沉默SERPINE1可增加MMP2的活性并降低COL13A1，而对N-钙黏蛋白和E-钙黏蛋白没有影响。我们使用Cu-TRZ与LOS的新型联合疗法归因于靶向ECM和IFP的SERPINE1的下调，对胃癌治疗非常有效。
