Hsa-miR-99a缺乏通过激活mTOR途径和诱导Th1/Th2失衡而导致MSI-H结直肠癌癌症进展
Hsa-miR-99a deficiency contributes to MSI-H colorectal cancer progression by activating the mTOR pathway and inducing Th1/Th2 imbalance.
摘要(中文译文)
hsa-miR-99a与多种恶性肿瘤的进展相关，包括结直肠癌（CRC）。本研究旨在阐明其在CRC中的功能及调控网络。研究分析了微卫星稳定（MSS）与微卫星高度不稳定（MSI-H）亚组之间hsa-miR-99a的差异表达。从TargetScan和miRWalk数据库中检索hsa-miR-99a的潜在靶mRNA。对重叠mRNA进行相关性分析，依据|相关系数|>0.3且p<0.05筛选候选基因。进行富集分析，突出关键通路，尤其是mTOR信号通路。比较MSS与MSI-H组之间的免疫浸润特征。通过RT-qPCR和Western blot验证hsa-miR-99a与mTOR通路相关基因之间的相关性。此外，采用酪胺信号放大（TSA）多重免疫组化（mIHC）技术表征MSI-H CRC样本的免疫微环境。hsa-miR-99a在MSS组中的表达显著高于MSI-H组。鉴定出12个关键靶基因，包括ATP2B2、ATP2B4、SLC8A1、KCNJ5、NTRK3、TNFRSF19、GHR、CXCL12、NTNG1、SDC2、SFRP1和PRICKLE2。免疫浸润分析显示MSS与MSI-H组之间24种细胞类型存在显著差异，包括Th1、Th2、Th17和效应记忆CD8+ T细胞。10个mTOR通路相关基因（ATP6V1G2、WNT2、WNT6、WNT9A、WNT9B、FZD1、FZD4、FZD8、IGF1、AKT3）与hsa-miR-99a表现出强相关性。其中，ATP6V1G2和WNT6在MSI-H组中上调。mIHC分析表明MSI-H CRC中Th1生物标志物减少，而Th2和Th17生物标志物增加。本研究鉴定了hsa-miR-99a在CRC中调控的关键基因及免疫微环境改变，为CRC治疗提供了新的见解和潜在治疗靶点。
Abstract
Hsa-miR-99a has been linked to the advancement of several malignancies, including colorectal cancer (CRC). This investigation seeks to elucidate its function and regulatory network in CRC. Differential expression of hsa-miR-99a was analyzed between microsatellite stable (MSS) and microsatellite instability-high (MSI-H) subgroups. Potential target mRNAs of hsa-miR-99a were retrieved from TargetScan and miRWalk databases. Overlapping mRNAs were subjected to correlation analysis, with candidate genes selected based on |correlation coefficient| > 0.3 and p < 0.05. Enrichment analyses were performed, highlighting key pathways, particularly mTOR signaling. Immune infiltration profiles were compared between MSS and MSI-H groups. Correlation between hsa-miR-99a and mTOR pathway-related genes was validated by RT-qPCR and Western blot. Additionally, multiplex immunohistochemistry (mIHC) with tyramine signal amplification (TSA) was used to characterize the immune microenvironment in MSI-H CRC samples. Hsa-miR-99a expression was significantly higher in MSS compared to MSI-H groups. Twelve key target genes were identified, including ATP2B2, ATP2B4, SLC8A1, KCNJ5, NTRK3, TNFRSF19, GHR, CXCL12, NTNG1, SDC2, SFRP1, and PRICKLE2. Immune infiltration analysis revealed significant differences in 24 cell types between MSS and MSI-H groups, including Th1, Th2, Th17, and effector memory CD8+ T cells. Ten mTOR pathway-related genes (ATP6V1G2, WNT2, WNT6, WNT9A, WNT9B, FZD1, FZD4, FZD8, IGF1, AKT3) exhibited strong correlation with hsa-miR-99a. Among these, ATP6V1G2 and WNT6 were upregulated in the MSI-H group. mIHC analysis indicated reduced Th1 but increased Th2 and Th17 biomarkers in MSI-H CRC. This study identified key genes and immune microenvironment alterations regulated by hsa-miR-99a in CRC, offering novel insights and potential therapeutic targets for CRC treatment.
如何引用
AMA
Xuejing Yang, Tingting Zhang, Hu Sun, Huijing Feng, Dong Song. Hsa-miR-99a deficiency contributes to MSI-H colorectal cancer progression by activating the mTOR pathway and inducing Th1/Th2 imbalance.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1796084.
APA
Xuejing Yang, Tingting Zhang, Hu Sun, Huijing Feng, Dong Song (2026). Hsa-miR-99a deficiency contributes to MSI-H colorectal cancer progression by activating the mTOR pathway and inducing Th1/Th2 imbalance.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1796084
GB/T 7714
Xuejing Yang, Tingting Zhang, Hu Sun, Huijing Feng, Dong Song. Hsa-miR-99a deficiency contributes to MSI-H colorectal cancer progression by activating the mTOR pathway and inducing Th1/Th2 imbalance.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1796084.
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