lncRNA ITGB8-AS1 functions as a ceRNA to promote colorectal cancer growth and migration through integrin-mediated focal adhesion signaling.
lncRNA ITGB8-AS1 functions as a ceRNA to promote colorectal cancer growth and migration through integrin-mediated focal adhesion signaling.
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DOI：
10.1016/j.ymthe.2021.08.011
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发表时间：
2022-02-02
期刊：
影响因子：
--
通讯作者：
Ye F
中科院分区：
文献类型：
--
作者：
Lin X;Zhuang S;Chen X;Du J;Zhong L;Ding J;Wang L;Yi J;Hu G;Tang G;Luo X;Liu W;Ye F
长非编码RNA(LncRNAs)在结直肠癌(CRC)的发生、发展中起重要作用。然而，大多数lncRNAs在结直肠癌中的功能及其分子机制尚不清楚。在此，我们发现incRNA ITGB8-AS1在结直肠癌中高表达。ITGB8-AS1基因敲除抑制了结直肠癌的细胞增殖、克隆形成和肿瘤生长，提示ITGB8-AS1具有致癌作用。转录分析和KEGG分析表明，对于ITGB8-AS1正调控的基因来说，粘着斑信号是最显著的丰富途径。一致地，ITGB8-AS1的敲除减弱了SRC、ERK和p38MAPK的磷酸化。从机制上讲，ITGB8-AS1可以结合miR-33b-5p和let-7c-5p/let-7d-5p，分别调节整合素家族基因ITGA3和ITGB3在细胞质中的表达。反义寡核苷酸(ASO)靶向ITGB8-AS1可显著抑制结直肠癌细胞增殖和肿瘤生长，提示ITGB8-AS1对结直肠癌有治疗潜力。此外，结直肠癌患者血浆中ITGB8-AS1水平较高，且与肿瘤分化程度、TNM分期、ITGA3、ITGB3水平呈正相关。综上所述，ITGB8-AS1作为一种竞争内源性RNA(CERNA)，通过调节粘着斑信号来调节结直肠癌的细胞增殖和肿瘤生长。靶向ITGB8-AS1能有效抑制结直肠癌细胞生长和肿瘤生长。晚期结直肠癌患者血浆ITGB8-AS1水平升高。因此，ITGB8-AS1可作为结直肠癌的潜在治疗靶点和循环生物标记物。大多数lncRNAs在结直肠癌中的功能及其分子机制尚不清楚。本工作鉴定了一种在CRC中高表达的特异性lncRNA，ITGB8-AS1。该lncRNA作为CERNA靶向整合素，促进结直肠癌的生长和转移。这项工作确定了一种新的结直肠癌治疗靶点和循环生物标志物。
Long non-coding RNAs (lncRNAs) play critical roles in tumorigenesis and progression of colorectal cancer (CRC). However, functions of most lncRNAs in CRC and their molecular mechanisms remain uncharacterized. Here we found that lncRNA ITGB8-AS1 was highly expressed in CRC. Knockdown of ITGB8-AS1 suppressed cell proliferation, colony formation, and tumor growth in CRC, suggesting oncogenic roles of ITGB8-AS1. Transcriptomic analysis followed by KEGG analysis revealed that focal adhesion signaling was the most significantly enriched pathway for genes positively regulated by ITGB8-AS1. Consistently, knockdown of ITGB8-AS1 attenuated the phosphorylation of SRC, ERK, and p38 MAPK. Mechanistically, ITGB8-AS1 could sponge miR-33b-5p and let-7c-5p/let-7d-5p to regulate the expression of integrin family genes ITGA3 and ITGB3, respectively, in the cytosol of cells. Targeting ITGB8-AS1 using antisense oligonucleotide (ASO) markedly reduced cell proliferation and tumor growth in CRC, indicating the therapeutic potential of ITGB8-AS1 in CRC. Furthermore, ITGB8-AS1 was easily detected in plasma of CRC patients, which was positively correlated with differentiation and TNM stage, as well as plasma levels of ITGA3 and ITGB3. In conclusion, ITGB8-AS1 functions as a competing endogenous RNA (ceRNA) to regulate cell proliferation and tumor growth of CRC via regulating focal adhesion signaling. Targeting ITGB8-AS1 is effective in suppressing CRC cell growth and tumor growth. Elevated plasma levels of ITGB8-AS1 were detected in advanced-stage CRC. Thus, ITGB8-AS1 could serve as a potential therapeutic target and circulating biomarker in CRC. Functions of most lncRNAs in CRC and their molecular mechanisms remain uncharacterized. This work characterized a specific lncRNA, ITGB8-AS1, highly expressed in CRC. This lncRNA functioned as a ceRNA to target integrins and promote CRC growth and metastasis. The work identified a novel therapeutic target and circulating biomarker for CRC.
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