Li Kexin, Huo Qingji, Minami Kazumasa, Tamari Keisuke, Ogawa Kazuhiko, Na Sungsoo, Fishel Melissa L, Li Bai-Yan, Yokota Hiroki
Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China.
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Cancers (Basel). 2023 Oct 10;15(20):4917. doi: 10.3390/cancers15204917.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.
胰腺导管腺癌（PDAC）是一种侵袭性癌症，生存率较低。我们通过利用预后致癌标志物探索了一种创新的治疗方法。我们不是抑制这些标志物基因，而是利用它们在细胞外区域的肿瘤修饰潜力。令人惊讶的是，许多在PDAC中高表达且与低生存率相关的蛋白质在细胞外环境中表现出肿瘤抑制特性。例如，与生存率降低相关的前列腺干细胞抗原（PSCA）在细胞外引入时起到肿瘤抑制作用。我们进行了体外试验以评估增殖和迁移，并评估了来自外周血单核细胞（PBMC）的细胞外因子对PDAC组织的肿瘤修饰能力。采用分子对接分析、免疫沉淀、蛋白质印迹和RNA干扰来研究调节机制。细胞外PSCA重组蛋白显著降低了PDAC细胞的活力、运动性和Transwell侵袭能力。其抗PDAC作用部分由间皮素（MSLN）介导，MSLN是另一种在PDAC中高表达的肿瘤相关抗原。细胞外PSCA的抗肿瘤作用与伊立替康、5-氟尿嘧啶和奥沙利铂等化疗药物的作用互补。PSCA在源自PBMC和T淋巴细胞的条件培养基中表达增加。这项研究揭示了PSCA矛盾的抗PDAC潜力，暗示了像PSCA这样的癌蛋白在PDAC抑制中的双重作用。
