MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

新兴的证据与肿瘤开发和前进显示出异常地表示的 microRNAs (miRNAs ) 的协会。然而，很少在胃的 carcinogenesis 对 miRNAs 的潜在的角色被知道。这里，我们执行了 miRNA microarray 屏蔽在配对的胃的癌症和他们的邻近的 nontumor 纸巾表示并且发现 miR-375 是的 miRNAs 差别极大地在胃的癌症纸巾的 downregulated。量的即时 PCR 分析证实那 miR-375 表情显著地从经历胃的切除术的病人与他们的 nontumor 对应物相比在超过 90% 主要胃的癌症被减少。miR-375 的 Overexpression 显著地在 vitro 并且在 vivo 禁止了胃的癌症房间增长。在胃的癌症房间的 miR-375 的强迫的表示显著地减少了 Janus kinase 的蛋白质水平 2 ( JAK2 )并且镇压带 JAK2 的 3 鈥? untranslated 区域的一个酶记者的活动，被预言的 miR-375-binding 地点的变化废除，显示那 JAK2 可以是 miR-375 目标基因。由由 RNAi 的 JAK2 的 AG490 或 silencing 的 JAK2 活动的任何一个抑制压制了类似于 miR-375 overexpression 的胃的癌症房间增长。而且， JAK2 的宫外的表示能部分颠倒 miR-375 引起的房间增长的抑制。最后，我们在胃的癌症发现了在 miR-375 表示和 JAK2 蛋白质水平之间的重要反的关联。因此，这些数据建议 miR-375 可以作为肿瘤 suppressor 工作由指向 JAK2 oncogene 潜在地调整胃的癌症房间增长，含有在胃的癌症的致病的 miR-375 的一个角色。

Bifidobacterium adolescentis orchestrates CD143^(+)cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1

Background The interplay between gut microbiota and tumor microenvironment(TME)in the pathogenesis of colorectal cancer(CRC)is not well explored.Here,we elucidated the functional role of Bifidobacterium adolescentis(B.a)on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts(CAFs)in CRC.Methods Different CRC animal models and various cell line models were established to explore the function of B.a on CRC.The single-cell RNA sequencing(scRNA-seq)or flow cytometry was used to detect the cell subsets in the TME of CRC.Western blot,quantitative real-time polymerase chain reaction(qRT-PCR),or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1(GAS1)on CD143+CAFs.Chromatin immunoprecipitation quantitative real-time PCR(CHIP-qPCR)was performed to investigate the regulation of transcription factor 4(TCF4)on GAS1.Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray.Results We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo.Supplementation with B.a suppressed ApcMin/+spontaneous or AOM/DSS-induced tumorigenesis in mice.scRNA-seq revealed that B.a facilitated a subset of CD143+CAFs by inhibiting the infiltration of Th2 cells,while promoting the TNF-alpha+B cells in TME.CD143+CAFs highly expressed GAS1 and exhibited tumor suppressive effect.Mechanistically,GAS1 was activated by the Wnt/β-catenin signaling in CD143+CAFs.B.a abundance was correlated with the expression level of CD143 and GAS1.The level of CD143+CAFs predicted the better survival outcome in CRC patients.Conclusions These results highlighted that B.a induced a new subset of CD143+CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.