Liu Jia, Fang Xiangming
Department of Gastroenterology, Puren Hospital Affiliated Wuhan University of Science and Technology, Wuhan, Hubei, China.
Biotechnol Appl Biochem. 2024 Dec;71(6):1316-1328. doi: 10.1002/bab.2631. Epub 2024 Jun 22.
A growing body of research highlights the role that N6-methyladenosine (mA) modification and circular RNAs (circRNAs) play in gastric cancer (GC) cases. However, studies elucidating the function and mechanism of the recently discovered circRNA hsa_circ_0112136 in GC are limited. This study aimed to examine the pathophysiology of GC progression due to fat mass and obesity-associated protein (FTO)-mediated N6-methyladenosine (mA) modification of hsa_circ_0112136. The hsa_circ_0112136 and FTO levels in the GC samples were analyzed using qRT-PCR. The Transwell invasion assay, wound healing assay, and CCK8 assays were employed to assess alterations in GC cell invasiveness, migration, and viability due to the aberrant regulation of hsa_circ_0112136 and FTO. Phosphorylated PI3K, AKT, and mTOR (the key proteins of the PI3K/AKT/mTOR pathway) were detected via western blotting after hsa_circ_0112136 suppression. A tumor transplantation mouse model was constructed to evaluate the suppression of hsa_circ_0112136's function in vivo. The correlation among hsa_circ_0112136 and FTO was identified using the MeRIP assay. Levels of hsa_circ_0112136 and FTO were evidently elevated in GC samples. Suppression of has_circ_0112136 reduced the viability, migration, and invasive ability of GC cells in vitro, as well as delayed tumor growth in vivo via suppression of the activation of the PI3K/AKT/mTOR pathway. FTO decreased hsa_circ_0112136 mA levels and enhanced hsa_circ_0112136 expression. Furthermore, FTO upregulation enhanced GC cell invasion, migration, and survival, which was reversed by hsa_circ_0112136 suppression. Our study proposes that hsa_circ_0112136 functions as a tumor promoter, facilitating the malignant progression of GC through mA modification (suppressed by FTO) and activating the PI3K/AKT/mTOR pathway. This suggests that targeting FTO-mA-hsa_circ_0112136-PI3K/AKT/mTOR may be a novel approach for GC intervention.
越来越多的研究强调了N6-甲基腺苷（m⁶A）修饰和环状RNA（circRNA）在胃癌（GC）病例中所起的作用。然而，关于最近发现的circRNA hsa_circ_0112136在GC中的功能和机制的研究却很有限。本研究旨在探讨脂肪量与肥胖相关蛋白（FTO）介导的hsa_circ_0112136的N6-甲基腺苷（m⁶A）修饰导致GC进展的病理生理学机制。采用qRT-PCR分析GC样本中hsa_circ_0112136和FTO的水平。运用Transwell侵袭试验、伤口愈合试验和CCK8试验评估由于hsa_circ_0112136和FTO的异常调控而导致的GC细胞侵袭性、迁移和活力的变化。在抑制hsa_circ_0112136后，通过蛋白质免疫印迹法检测磷酸化的PI3K、AKT和mTOR（PI3K/AKT/mTOR通路的关键蛋白）。构建肿瘤移植小鼠模型以评估hsa_circ_0112136在体内功能的抑制情况。使用MeRIP试验确定hsa_circ_0112136与FTO之间的相关性。GC样本中hsa_circ_0112136和FTO的水平明显升高。抑制hsa_circ_0112136可降低GC细胞在体外的活力、迁移和侵袭能力，并通过抑制PI3K/AKT/mTOR通路的激活在体内延缓肿瘤生长。FTO降低了hsa_circ_0112136的m⁶A水平并增强了hsa_circ_0112136的表达。此外，FTO的上调增强了GC细胞的侵袭、迁移和存活能力，而hsa_circ_0112136的抑制可逆转这种作用。我们的研究表明，hsa_circ_0112136作为一种肿瘤促进因子，通过m⁶A修饰（被FTO抑制）促进GC的恶性进展并激活PI3K/AKT/mTOR通路。这表明靶向FTO-m⁶A-hsa_circ_0112136-PI3K/AKT/mTOR可能是GC干预的一种新方法。
