Sun Shuning, Meng Lin, Xing Xiaofang, Li Ningning, Song Qian, Qiao Dongbo, Qu Like, Liu Caiyun, An Guo, Li Zhongwu, Shou Chenchao, Lian Shenyi
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.
J Cancer. 2023 Aug 21;14(13):2585-2595. doi: 10.7150/jca.81702. eCollection 2023.
Colon cancer is the one of leading causes of cancer-related death. Chemotherapy, radiotherapy and immunotherapy will be the mainstream in inoperable advanced cancer in clinics. Precision treatment is still lack in colon cancer. We developed a series of mAbs targeting PRL-3 through different types of immunogens. The binding domains of mAbs were identified through the ELISA and Western blotting experiments. The antitumor activity of mAbs was verified by cell proliferation, migration and invasion experiments. Xenograft subcutaneous and metastatic models and patient derived Xenograft (PDX) model were established. mAb 12G12 targeting 77-120AA exhibited inhibition in migration and invasion experiments. 12G12 inhibited the migration of multiple types of cancer cells, including colon cancer, gastric cancer, esophagus cancer, liver cancer, lung cancer and pancreatic cancer cells. 12G12 decreased the tumor growth and metastasis in Xenograft subcutaneous and metastatic tumor model, respectively. The antitumor activity of mAb 12G12 was also confirmed in PDX model of gastric cancer. PRL-3 interacted with Golgi protein TMED10. Knockdown of TMED10 expression attenuated the cell migration triggered by purified GST-PRL-3 protein. Our results confirmed the antitumor activity of mAb 12G12 in colorectal adenocarcinoma and provided a new potential targeted therapy of colon cancer.
结肠癌是癌症相关死亡的主要原因之一。化疗、放疗和免疫疗法将成为临床上不可切除的晚期癌症的主流治疗方法。结肠癌仍缺乏精准治疗。我们通过不同类型的免疫原开发了一系列靶向PRL-3的单克隆抗体。通过ELISA和蛋白质印迹实验鉴定了单克隆抗体的结合结构域。通过细胞增殖、迁移和侵袭实验验证了单克隆抗体的抗肿瘤活性。建立了异种移植皮下和转移模型以及患者来源的异种移植（PDX）模型。靶向77-120AA的单克隆抗体12G12在迁移和侵袭实验中表现出抑制作用。12G12抑制多种类型癌细胞的迁移，包括结肠癌细胞、胃癌细胞、食管癌细胞、肝癌细胞、肺癌细胞和胰腺癌细胞。12G12分别在异种移植皮下和转移瘤模型中降低了肿瘤生长和转移。单克隆抗体12G12的抗肿瘤活性在胃癌的PDX模型中也得到了证实。PRL-3与高尔基体蛋白TMED10相互作用。敲低TMED10的表达减弱了纯化的GST-PRL-3蛋白触发的细胞迁移。我们的结果证实了单克隆抗体12G12在结直肠癌中的抗肿瘤活性，并为结肠癌提供了一种新的潜在靶向治疗方法。
