Abstract：
LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. M6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440 nt) and T5 (2440-2743 nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.
摘要：
LncRNA在癌症进展和靶向中起着至关重要的作用，但很难确定参与结直肠癌(CRC)进展的关键lncRNAs.我们使用21对IV期CRC组织和邻近正常组织将FAM83H-AS1鉴定为肿瘤促进相关lncRNA。体外和体内实验表明，在CRC细胞中敲低FAM83H-AS1抑制肿瘤的增殖和转移，反之亦然。m6A修饰对于通过作者METTL3和读者IGF2BP2/IGFBP3的FAM83H-AS1RNA稳定性至关重要。PTBP1-一种RNA结合蛋白-负责CRC中的FAM83H-AS1功能。FAM83H-AS1的外显子4上的T4(1770-2440nt)和T5(2440-2743nt)提供了PTBP1RRM2相互作用的平台。我们的结果表明，m6A修饰通过磷酸化PTBP1对其RNA剪接作用失调FAM83H-AS1致癌作用。在患者来源的异种移植模型中，ASO-FAM83H-AS1显著抑制胃肠道（GI）肿瘤的生长，不仅是CRC，还有GC和ESCC。ASO-FAM83H-AS1和奥沙利铂/顺铂的组合与单独使用任一种药剂的治疗相比显著抑制肿瘤生长。值得注意的是,所有这三种胃肠道癌均有病理完全缓解。我们的研究结果表明，FAM83H-AS1靶向治疗将使主要接受铂类药物治疗的胃肠道肿瘤患者受益。
