长非编码 RNA LINC00346 通过海绵吸附 miR-188-3p 来解除 BRD4 表达的抑制作用，从而促进胰腺癌的生长和吉西他滨耐药性。
Long non-coding RNA LINC00346 promotes pancreatic cancer growth and gemcitabine resistance by sponging miR-188-3p to derepress BRD4 expression.
机构信息
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
出版信息
J Exp Clin Cancer Res. 2019 Feb 6;38(1):60. doi: 10.1186/s13046-019-1055-9.
BACKGROUND
Long non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. However, its biological function in pancreatic cancer has not yet been determined. In this study, we attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer.
METHODS
The effects of overexpression and knockdown of LINC00346 on the proliferation, cell cycle progression, apoptosis, and gemcitabine resistance were investigated. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation assay were performed to search for potential microRNAs (miRs) that can interact with LINC00346.
RESULTS
Overexpression of LINC00346 significantly enhanced the proliferation, colony formation, and tumorigenesis of pancreatic cancer cells. Conversely, knockdown of LINC00346 suppressed pancreatic cancer cell proliferation and caused a cell-cycle arrest at the G2/M-phase. Depletion of LINC00346 also enhanced gemcitabine sensitivity in pancreatic cancer cells both in vitro and in vivo. Mechanistic investigation revealed that LINC00346 acted as a sponge for miR-188-3p and blocked the repression of BRD4 by miR-188-3p in pancreatic cancer cells. Clinical evidence indicated a negative correlation between LINC00346 and miR-188-3p in pancreatic cancer specimens. Rescue experiments showed that LINC00346 attenuated the growth-suppressing and chemosensitizing effects of miR-188-3p on pancreatic cancer cells. In addition, silencing of BRD4 significantly inhibited LINC00346-induced pancreatic cancer cell proliferation and colony formation.
CONCLUSIONS
LINC00346 shows the ability to promote pancreatic cancer growth and gemcitabine resistance, which is in part mediated by antagonization of miR-188-3p and induction of BRD4. Targeting LINC00346 may improve gemcitabine-based therapeutic efficacy.
背景
长链非编码 RNA LINC00346 最近被认为是胰腺癌的预后标志物。然而，其在胰腺癌中的生物学功能尚未确定。在这项研究中，我们试图确定 LINC00346 在调节胰腺癌侵袭性中的作用。
方法
研究了过表达和敲低 LINC00346 对胰腺癌细胞增殖、细胞周期进程、凋亡和吉西他滨耐药性的影响。进行了生物信息学分析、荧光素酶报告基因检测和 RNA 免疫沉淀检测，以寻找可能与 LINC00346 相互作用的 microRNAs（miRs）。
结果
过表达 LINC00346 显著增强了胰腺癌细胞的增殖、集落形成和致瘤性。相反，敲低 LINC00346 抑制了胰腺癌细胞的增殖，并导致细胞周期停滞在 G2/M 期。在体外和体内，敲低 LINC00346 也增强了胰腺癌细胞对吉西他滨的敏感性。机制研究表明，LINC00346 作为 miR-188-3p 的海绵，阻断了 miR-188-3p 对胰腺癌细胞中 BRD4 的抑制作用。临床证据表明，LINC00346 在胰腺癌细胞标本中与 miR-188-3p 呈负相关。挽救实验表明，LINC00346 减弱了 miR-188-3p 对胰腺癌细胞生长抑制和化疗增敏的作用。此外，沉默 BRD4 显著抑制了 LINC00346 诱导的胰腺癌细胞增殖和集落形成。
结论
LINC00346 表现出促进胰腺癌生长和吉西他滨耐药的能力，部分是通过拮抗 miR-188-3p 和诱导 BRD4 来实现的。靶向 LINC00346 可能提高基于吉西他滨的治疗疗效。
Zotero 插件