Extracellular vesicle expansion of PMIS-miR-210 expression inhibits colorectal tumour growth via apoptosis and an XIST/NME1 regulatory mechanism.
Extracellular vesicle expansion of PMIS-miR-210 expression inhibits colorectal tumour growth via apoptosis and an XIST/NME1 regulatory mechanism.
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PMIS-miR-210表达的胞外囊泡扩张通过细胞凋亡和XIST/NME1调节机制抑制结直肠肿瘤的生长。
DOI：
10.1002/ctm2.1037
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发表时间：
2022-09
影响因子：
10.6
通讯作者：
Amendt, Brad A.
中科院分区：
文献类型：
--
作者：
Eliason, Steven;Hong, Liu;Sweat, Yan;Chalkley, Camille;Cao, Huojun;Liu, Qi;Qi, Hank;Xu, Hongwei;Zhan, Fenghuang;Amendt, Brad A.
关键词：
结直肠癌（CRC）死亡率高，治疗这些癌症的治疗方法多种多样，并取决于肿瘤的代谢状态。CRC肿瘤的特征已经确定了几种生物标志物，包括microRNA。microRNA-210（miR-210）水平与CRC生存率直接相关。miR-210在转移性结肠癌细胞中的表达高于非转移性和正常结肠上皮。因此，抑制CRC中miR-210表达的有效方法可能会为治疗提供新的进展。在几种转移性和非转移性细胞系中测定miR的表达。使用PMIS-miR-210在转导细胞中抑制miR-210表达，所述转导细胞被移植到异种移植小鼠中。在单独的实验中，允许CRC肿瘤在异种移植小鼠中生长，并用PMIS-miR-210的治疗性注射进行治疗。分子和生物化学实验确定了miR-210抑制作用靶向的几种新途径。 miR-210抑制可以显著降低异种移植小鼠模型中植入的结肠癌细胞的肿瘤生长。PMIS-miR-210直接给予现有肿瘤可以抑制NSG和Foxn 1 nu/j小鼠模型中的肿瘤生长，并且比卡培他滨治疗更有效。肿瘤细胞进一步通过细胞外囊泡将PMIS-miR-210抑制剂转移到邻近细胞，以在整个肿瘤中抑制miR-210。miR-210抑制激活裂解的caspase 3凋亡途径以减少肿瘤形成。我们证明了长非编码转录物XIST受miR-210调控，与CRC肿瘤中XIST表达降低相关。XIST作为miR-210的竞争性内源性RNA，降低XIST水平，miR-210抑制增加细胞核和细胞质中的XIST转录物。NME 1表达的增加与XIST在NME 1近端启动子中的H3 K4 me 3和H3 K27 ac修饰相关。PMIS-miR-210抑制剂直接应用于生长肿瘤可能是一种有效的结直肠癌治疗方法。一种新的120 nt microRNA抑制剂治疗剂对细胞具有特异性、稳定性、有效性和无毒性，将该抑制剂注射到生长的结直肠肿瘤中可抑制和减少肿瘤生长。 miR-210抑制激活细胞凋亡、XIST和NME 1以减少肿瘤生长这种方法突出了基于质粒的microRNA抑制系统（PMIS）在治疗肿瘤方面的治疗应用。
Colorectal cancer (CRC) has a high mortality rate, and therapeutic approaches to treat these cancers are varied and depend on the metabolic state of the tumour. Profiles of CRC tumours have identified several biomarkers, including microRNAs. microRNA‐210 (miR‐210) levels are directly correlated with CRC survival. miR‐210 expression is higher in metastatic colon cancer cells versus non‐metastatic and normal colon epithelium. Therefore, efficient methods to inhibit miR‐210 expression in CRC may provide new advances in treatments. Expression of miRs was determined in several metastatic and non‐metastatic cell lines. miR‐210 expression was inhibited using PMIS‐miR‐210 in transduced cells, which were transplanted into xenograft mice. In separate experiments, CRC tumours were allowed to grow in xenograft mice and treated with therapeutic injections of PMIS‐miR‐210. Molecular and biochemical experiments identified several new pathways targeted by miR‐210 inhibition. miR‐210 inhibition can significantly reduce tumour growth of implanted colon cancer cells in xenograft mouse models. The direct administration of PMIS‐miR‐210 to existing tumours can inhibit tumour growth in both NSG and Foxn1nu/j mouse models and is more efficacious than capecitabine treatments. Tumour cells further transfer the PMIS‐miR‐210 inhibitor to neighbouring cells by extracellular vesicles to inhibit miR‐210 throughout the tumour. miR‐210 inhibition activates the cleaved caspase 3 apoptotic pathway to reduce tumour formation. We demonstrate that the long non‐coding transcript XIST is regulated by miR‐210 correlating with decreased XIST expression in CRC tumours. XIST acts as a competing endogenous RNA for miR‐210, which reduces XIST levels and miR‐210 inhibition increases XIST transcripts in the nucleus and cytoplasm. The increased expression of NME1 is associated with H3K4me3 and H3K27ac modifications in the NME1 proximal promoter by XIST. Direct application of the PMIS‐miR‐210 inhibitor to growing tumours may be an effective colorectal cancer therapeutic. A new 120 nt microRNA inhibitor therapeutic is specific, stable, efficient and non‐toxic to cells Injection of the inhibitor into growing colorectal tumors inhibits and reduces tumor growth. miR‐210 inhibition activates apoptosis, XIST and NME1 to reduce tumor growth This approach highlights the therapeutic application of the plasmid‐based microRNA inhibition system (PMIS) for treating tumors.
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