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长链非编码RNA LBX2-AS1促进结直肠癌进展及5-氟尿嘧啶耐药。

LncRNA LBX2-AS1 promotes colorectal cancer progression and 5-fluorouracil resistance.

作者信息

Ma Yu-Nan, Hong Yong-Gang, Yu Guan-Yu, Jiang Si-Yuan, Zhao Bo-Lun, Guo An, Wang Yao, Cui Xiao-Ming, Hao Li-Qiang, Zheng Hao

机构信息

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing, 100142, China.

Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.

出版信息

Cancer Cell Int. 2021 Sep 17;21(1):501. doi: 10.1186/s12935-021-02209-y.

DOI:10.1186/s12935-021-02209-y
PMID:34535128
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8449476/
Abstract

BACKGROUND

Recent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined.

METHODS

LBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance.

RESULTS

Data from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy.

CONCLUSIONS

Together these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.

摘要

背景

最近的报告表明，长链非编码RNA LBX2反义RNA 1（LBX2-AS1）在癌症进展中起重要调节作用，但其在结直肠癌（CRC）中的意义仍未确定。

方法

从GEPIA数据库和CRC组织中确定LBX2-AS1在CRC中的表达水平，以研究其临床相关性。甲基化RNA免疫沉淀PCR（meRIP-PCR）分析研究了m6A在LBX2-AS1功能中的分子机制。功能丧失实验用于确定LBX2-AS1在CRC进展中的作用。通过RNA免疫沉淀评估LBX2-AS1的竞争性内源性RNA（ceRNA）功能。利用体外和人源肿瘤异种移植（PDX）模型确定LBX2-AS1是否促进5-氟尿嘧啶耐药性。

结果

来自TCGA和我们机构患者队列的数据表明，与相邻正常结肠组织相比，大多数CRC组织中LBX2-AS1水平显著上调。此外，LBX2-AS1水平与侵袭性疾病特征呈正相关，是患者总体生存的独立预后指标。机制研究表明，CRC中LBX2-AS1的增加是由METTL3依赖性m6A甲基化介导的。体外实验表明，敲低LBX2-AS1可抑制CRC的增殖、迁移和侵袭，这种表型与LBX2-AS1介导的AKT1调节有关，LBX2-AS1作为ceRNA海绵吸附miR-422a。对患者来源的CRC异种移植的体外分析表明，低LBX2-AS1表达的病例表现出对5-氟尿嘧啶的反应性，临床研究证实，低LBX2-AS1表达与5-氟尿嘧啶治疗的临床获益改善相关。

结论

这些结果共同表明，LBX2-AS1可能是CRC患者的治疗靶点和5-氟尿嘧啶获益的预测指标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/0d8fdf384364/12935_2021_2209_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/492f48c3d39f/12935_2021_2209_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/9013415bfcab/12935_2021_2209_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/411ef1e13c91/12935_2021_2209_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/95ba62914b60/12935_2021_2209_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/e608f2428395/12935_2021_2209_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/d66acbf4faef/12935_2021_2209_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/0d8fdf384364/12935_2021_2209_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/492f48c3d39f/12935_2021_2209_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/9013415bfcab/12935_2021_2209_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/411ef1e13c91/12935_2021_2209_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/95ba62914b60/12935_2021_2209_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/e608f2428395/12935_2021_2209_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/d66acbf4faef/12935_2021_2209_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dde/8449476/0d8fdf384364/12935_2021_2209_Fig7_HTML.jpg

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