Satow Reiko, Kashiwaba Yuki, Okao Misaki, Takano Shin, Aiga Yuna, Yoneda Atsuko, Hosomichi Kazuyoshi, Fukami Kiyoko
Laboratory of Computational Genomics, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Japan.
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Japan.
FEBS J. 2025 Aug;292(15):4057-4068. doi: 10.1111/febs.70125. Epub 2025 May 3.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with few effective therapies available. We previously determined the essential role of Zic family member 5 (ZIC5) in the survival of PDAC cells. In this study, we showed that targeting ZIC5 can effectively shrink PDAC tumors treated with gemcitabine in vivo and investigated the molecular mechanisms involved. When tumor-bearing mice were injected intravenously with ZIC5-targeting small interfering RNA, tumor volume was significantly reduced by gemcitabine treatment. RNA-sequencing analysis was used to identify the genes affected by ZIC5 knockdown. Among these, we selected the genes whose mRNA expression levels correlated with that of ZIC5 in pancreatic cancer and those associated with poor prognosis in patients with pancreatic cancer. Further analysis revealed that RIO kinase 3 (RIOK3) promotes PDAC cell survival, whereas ALDH3B1, PTGES, and TUFT1 contribute to gemcitabine resistance in MiaPaca-2 cells. We identified RIOK3 as a direct target gene of ZIC5 using ChIP and luciferase assays. Furthermore, stable expression of RIOK3 in PANC-1 cells reversed the reduction in cell number following ZIC5 knockdown. These findings highlight RIOK3 as a critical target of ZIC5, which is involved in survival signaling in PDAC cells.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，可用的有效治疗方法很少。我们之前确定了锌指蛋白家族成员5（ZIC5）在PDAC细胞存活中的关键作用。在本研究中，我们表明靶向ZIC5可有效缩小体内接受吉西他滨治疗的PDAC肿瘤，并研究了其中涉及的分子机制。当给荷瘤小鼠静脉注射靶向ZIC5的小干扰RNA时，吉西他滨治疗可显著减小肿瘤体积。RNA测序分析用于鉴定受ZIC5敲低影响的基因。在这些基因中，我们选择了那些mRNA表达水平与胰腺癌中ZIC5的表达水平相关以及与胰腺癌患者预后不良相关的基因。进一步分析表明，RIO激酶3（RIOK3）促进PDAC细胞存活，而醛脱氢酶3B1（ALDH3B1）、前列腺素E合成酶（PTGES）和簇毛蛋白1（TUFT1）在MiaPaca-2细胞中导致吉西他滨耐药。我们使用染色质免疫沉淀和荧光素酶测定法确定RIOK3是ZIC5的直接靶基因。此外，在PANC-1细胞中稳定表达RIOK3可逆转ZIC5敲低后细胞数量的减少。这些发现突出了RIOK3作为ZIC5的关键靶点，其参与PDAC细胞的存活信号传导。
