Liu Junhong, Ye Lin, Lin Kangqiang, Zhong Tieshan, Luo Jiguang, Wang Tao, Suo Liya, Mo Qingrong, Li Shuqun, Chen Qian, Yu Yaqun
Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541002, China.
Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
Mol Cell Biochem. 2023 Aug;478(8):1727-1742. doi: 10.1007/s11010-022-04617-8. Epub 2022 Dec 24.
Pancreatic cancer (PC) is one of the most aggressive malignant tumors in human beings. Tumor capacity of evading immune-mediated lysis is a critical step in PC malignant progression. We aimed to evaluate the underlying regulatory mechanism of miR-4299 in the proliferation, metastasis, apoptosis, and immune escape in PC. miR-4299 and ADAM17 expressions in PC tissues and cell lines were detected using qRT-PCR. MTT assay and flow cytometry were used to detect cell viability and apoptosis, respectively. A luciferase reporter gene assay was conducted to confirm the targeted relationship between miR-4299 and ADAM17. Xenograft tumors in nude mice were used to detect tumorigenesis in vivo. PC cells were co-cultured with NK cells for determining the immune escape ability. NKG2D-positive rate of NK cells was detected using flow cytometry; NK cell-killing ability was detected using MTT assay. miR-4299 was downregulated in PC tissues and cell lines. miR-4299 inhibited PC cell proliferation and invasion, promoted cell apoptosis, and reduced PC tumor growth in vivo. ADAM17 3'UTR directly bound to miR-4299. ADAM17 overexpression could reverse miR-4299 effects on PC cell viability, invasion, apoptosis, and immune escape. miR-4299 exerted suppressive effects on PC cell proliferation, invasion, and immune escape via targeting ADAM17 expression. This study revealed a novel miR-4299/ADAM17 axis-modulating PC progression and proposed to concern the immune regulatory mechanism of miRNAs in PC development.
胰腺癌（PC）是人类最具侵袭性的恶性肿瘤之一。肿瘤逃避免疫介导裂解的能力是PC恶性进展的关键步骤。我们旨在评估miR - 4299在PC增殖、转移、凋亡和免疫逃逸中的潜在调控机制。采用qRT - PCR检测PC组织和细胞系中miR - 4299和ADAM17的表达。分别用MTT法和流式细胞术检测细胞活力和凋亡。进行荧光素酶报告基因检测以确认miR - 4299与ADAM17之间的靶向关系。利用裸鼠体内异种移植瘤检测肿瘤发生情况。将PC细胞与NK细胞共培养以确定免疫逃逸能力。用流式细胞术检测NK细胞的NKG2D阳性率；用MTT法检测NK细胞的杀伤能力。miR - 4299在PC组织和细胞系中表达下调。miR - 4299抑制PC细胞增殖和侵袭，促进细胞凋亡，并在体内降低PC肿瘤生长。ADAM17的3'UTR直接与miR - 4299结合。ADAM17过表达可逆转miR - 4299对PC细胞活力、侵袭、凋亡和免疫逃逸的影响。miR - 4299通过靶向ADAM17表达对PC细胞增殖、侵袭和免疫逃逸发挥抑制作用。本研究揭示了一种新的调节PC进展的miR - 4299/ADAM17轴，并提出关注miRNAs在PC发生发展中的免疫调节机制。
