Myint Khine, Chuang Linda Shyue Huey, Teh Yu Xuan, Mawan Nur Astiana, Shi Edward Jizhong, Mok Michelle Meng Huang, Nuttonmanit Napat, Matsuo Junichi, Li Ying, Yang Henry, Okabe Atsushi, Kaneda Atsushi, Osato Motomi, So Jimmy Bok-Yan, Yong Wei Peng, Tan Patrick, Yeoh Khay Guan, Ito Yoshiaki
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore.
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
iScience. 2022 Sep 23;25(10):105194. doi: 10.1016/j.isci.2022.105194. eCollection 2022 Oct 21.
We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach and that IQGAP3 expression is robustly induced in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated IQGAP3 expression in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes IQGAP3 upregulation in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both decreasing during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon re-expression of IGF2BP1 during carcinogenesis. IGF2BP1 binds and stabilizes mA-modified IQGAP3 transcripts. Downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
我们之前报道过，IQGAP3是胃中快速增殖的峡部干细胞中的一种重要干细胞因子，并且在终末分化的主细胞和组织损伤后的去分化细胞中，IQGAP3的表达被强烈诱导。IQGAP3在癌症中的表达升高及其与转移的关联表明，IQGAP3在增殖性癌症干细胞中起重要作用。癌症中IQGAP3上调的原因尚不清楚。在此，我们表明IGF2BP1和IQGAP3的表达水平在囊胚中最高，在成年期两者均下降。这表明IQGAP3与IGF2BP1一样，是一种早期发育基因，在致癌过程中因IGF2BP1的重新表达而异常上调。IGF2BP1结合并稳定mA修饰的IQGAP3转录本。IGF2BP1的下游靶点，即SRF和FOXM1，也上调IQGAP3的表达。IQGAP3的这些多层次调控可能防止不适当的干细胞增殖，为抑制IQGAP3驱动的恶性生长提供了额外的药物靶点。
