From the Departments of Hepatobiliary and Pancreatic Surgery II.
Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China.
Pancreas. 2021 Feb 1;50(2):227-234. doi: 10.1097/MPA.0000000000001747.
Elucidation of the regulatory mechanisms of gemcitabine sensitivity is needed to improve the therapeutic effects of this drug in pancreatic cancer.
PANC-1 cells were transfected with small hairpin RNA against PVT1 or microRNA (miR)-143 mimics or inhibitor. The gemcitabine sensitivity of pancreatic cancer was evaluated. Autophagosomes were analyzed with an immunofluorescence assay. Cell viability and proliferation were examined with MTT assays. Quantitative reverse transcription-polymerase chain reaction and Western blotting were used to analyze the expression of PVT1, miR-143, HIF-1α, VMP1, LC3I/II, p62, and Beclin-1. The interactions of PVT1/miR-143 and miR-143/HIF-1α were assessed by dual-luciferase reporter assays.
PVT1 was upregulated while miR-143 was downregulated in pancreatic cancer. Both PVT1 knockdown and miR-143 overexpression suppressed autophagy and improved gemcitabine sensitivity in pancreatic cancer. PVT1 directly sponged miR-143 to regulate HIF-1α expression. MiR-143 inhibitor reversed the effect of PVT1 knockdown on autophagy and gemcitabine sensitivity.
PVT1 knockdown inhibited autophagy and improved gemcitabine sensitivity via the miR-143/HIF-1α/VMP1 axis in pancreatic cancer. Our investigation elucidated a novel regulatory mechanism of gemcitabine sensitivity and may contribute to improve the therapeutic effects of chemotherapy drugs on pancreatic cancer.
阐明吉西他滨敏感性的调控机制，以提高该药在胰腺癌中的治疗效果。
用小发夹 RNA 转染 PANC-1 细胞靶向 PVT1 或 microRNA（miR）-143 模拟物或抑制剂。评估胰腺癌对吉西他滨的敏感性。用免疫荧光法分析自噬体。用 MTT 法检测细胞活力和增殖。用定量逆转录聚合酶链反应和 Western blot 分析 PVT1、miR-143、HIF-1α、VMP1、LC3I/II、p62 和 Beclin-1 的表达。通过双荧光素酶报告基因检测评估 PVT1/miR-143 和 miR-143/HIF-1α 的相互作用。
胰腺癌中 PVT1 上调而 miR-143 下调。PVT1 敲低和 miR-143 过表达均抑制自噬并提高胰腺癌对吉西他滨的敏感性。PVT1 直接吸附 miR-143 调节 HIF-1α 的表达。miR-143 抑制剂逆转了 PVT1 敲低对自噬和吉西他滨敏感性的影响。
PVT1 敲低通过 miR-143/HIF-1α/VMP1 轴抑制自噬并提高胰腺癌对吉西他滨的敏感性。我们的研究阐明了吉西他滨敏感性的新调控机制，可能有助于提高化疗药物对胰腺癌的治疗效果。
