PO.MCB08.04 · 分子与细胞生物学
胃癌腹膜转移中EMT与Hippo通路活性的整合分析
Integrative analysis of EMT and hippo pathway activity in gastric cancer peritoneal metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胃癌（GC）是最具侵袭性的恶性肿瘤之一，患者预后不良往往源于频繁的腹膜转移。上皮-间质转化（EMT）在这一转移过程中发挥关键作用。近期研究强调了Hippo信号通路在调控EMT和肿瘤进展中的参与作用。然而，Hippo信号组分与ARID1A（一种在GC中频繁突变或缺失的关键染色质重塑因子）之间的分子相互作用仍知之甚少。本研究探讨了胃癌腹膜转移（GCPM）中Hippo通路失调与ARID1A改变之间的关系。对47株CIN和GS样亚型的GCPM细胞系进行了基因组和分子谱分析。层次聚类将细胞系分为EMT组与非EMT组，以及Hippo组与非Hippo组。采用单样本基因集富集分析（ssGSEA）计算EMT和Hippo通路活性评分。在mRNA和蛋白水平分析了EMT、Hippo通路及ARID1A相关基因的表达。通过transwell侵袭实验评估侵袭性，并采用细胞活力实验评估对YAP抑制剂CA3（CIL56）的敏感性。层次聚类将细胞系分为EMT组（n=34）和非EMT组（n=13）。EMT组富集于EMT、YAP和TGF-beta通路相关基因集，并表现出显著更高的EMT和Hippo通路评分（p<0.05）。这些分子特征伴随着明显更高的侵袭能力。CA3敏感性在各PMGC细胞系间差异很大，平均IC50为0.65 μM（范围0.07-1.98 μM）。在TCGA分子亚型、EMT或Hippo亚组之间未观察到CA3敏感性的显著差异。值得注意的是，与ARID1A野生型细胞系相比，ARID1A改变型细胞系对YAP抑制剂CA3表现出显著增强的敏感性，提示ARID1A缺陷型肿瘤对YAP活性存在依赖性。综上所述，这些发现表明ARID1A改变增强了对Hippo-YAP通路的依赖性，并在GCPM中赋予对YAP抑制的更高敏感性。因此，ARID1A缺陷型肿瘤可能受益于靶向Hippo-YAP轴的治疗策略。
查看英文原文 English abstract
Gastric cancer (GC) is one of the most aggressive malignancies, with poor patient outcomes often due to frequent peritoneal metastasis. Epithelial-mesenchymal transition (EMT) plays a pivotal role in this metastatic process. Recent studies highlight the involvement of the Hippo signaling pathway in regulating EMT and tumor progression. However, the molecular interplay between Hippo signaling components and ARID1A , a key chromatin remodeling factor frequently mutated or lost in GC, remains poorly understood. This study investigates the relationship between Hippo pathway dysregulation and ARID1A alteration in gastric cancer peritoneal metastasis (GCPM). Genomic and molecular profiling were performed on 47 GCPM cell lines of CIN and GS-like subtypes. Hierarchical clustering classified the cell lines into EMT and non-EMT groups, as well as into Hippo and non-Hippo groups. EMT and Hippo pathway activity scores were calculated using single-sample gene set enrichment analysis (ssGSEA). Expression of genes related to EMT, Hippo pathways, and ARID1A was analyzed at mRNA and protein levels. Invasiveness was evaluated by transwell invasion assays, and sensitivity to the YAP inhibitor CA3 (CIL56) was assessed using cell viability assays. Hierarchical clustering divided the cell lines into EMT (n=34) and non-EMT (n=13) groups. The EMT group was enriched in gene sets related to EMT, YAP, and TGF-beta pathways and exhibited significantly higher EMT and Hippo pathway scores ( p < 0.05). These molecular features were accompanied by markedly higher invasive capacity. CA3 sensitivity varied widely across PMGC cell lines, with a mean IC 50 of 0.65 μM (range, 0.07-1.98 μM). No significant differences in CA3 sensitivity were observed across TCGA molecular subtypes, EMT, or Hippo subgroups. Notably, ARID1A -altered cell lines demonstrated significantly enhanced sensitivity to the YAP inhibitor CA3 compared with ARID1A -wild-type lines, suggesting a dependency on YAP activity in ARID1A -deficient tumors. Together, these findings indicate that ARID1A alterations enhance Hippo-YAP pathway dependence and confer increased sensitivity to YAP inhibition in GCPM. ARID1A -deficient tumors may therefore benefit from therapeutic strategies targeting the Hippo-YAP axis.
利益披露 Disclosure
J. Park, None..
W. Kwon, None..
C. Park, None..
T. Kim, None..
J. Che, None.