基因敲除
癌症研究
生物
癌变
克拉斯
MAPK/ERK通路
转移
细胞生长
间质细胞
信号转导
肿瘤微环境
癌症
细胞培养
细胞生物学
遗传学
结直肠癌
肿瘤细胞
作者
Mitsuhiro Shimura,Junichi Matsuo,ShuChin Pang,Nawaphat Jangphattananont,Aashiq Hussain,Muhammad Bakhait Bin Rahmat,Jung-Won Lee,Daisuke Douchi,Jasmine Jie Lin Tong,Khine Nyein Myint,Supriya Srivastava,Ming Teh,Vivien Koh,Wei Peng Yong,Jimmy Bok Yan So,Patrick Tan,Khay Guan Yeoh,Michiaki Unno,Linda Shyue Huey Chuang,Yoshiaki Ito
出处
期刊:Gut
[BMJ]
日期:2024-10-22
卷期号:: gutjnl-330390
标识
DOI:10.1136/gutjnl-2023-330390
摘要
Background The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear. Objective We define the function of IQGAP3 in gastric cancer (GC) development and progression. Design We studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours. Results Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions. Conclusion IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.
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