Hongqiao International Research Institution, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, the Second Military Medical University, Shanghai, China.
Cancer Biol Ther. 2021 Apr 3;22(4):311-323. doi: 10.1080/15384047.2021.1905138. Epub 2021 Apr 20.
In China, gastric cancer (GC) ranks first in the incidence of all malignant tumors. With high recurrence and distant metastasis, GC has caused considerable mortalities. LncRNA long intergenic non-protein-coding RNA 668 (LINC00668) has been reported to be upregulated in GC cells and predict poor prognosis of GC patients. However, the mechanism of LINC00668 has not been fully investigated in GC. This study aimed to investigate the role of LINC00668 in GC. We found that LINC00668 level was upregulated in GC tissue and cells and predicted poor prognosis. Functionally, LINC00668 knockdown suppressed GC cell migration and invasion. Additionally, LINC00668 knockdown inhibited epithelial to mesenchymal transition (EMT) process. PKN2 exerts similar effects with LINC00668 in GC cells. LINC00668 knockdown suppressed tumor growth and metastasis . Mechanistically, HuR was predicted to bind with LINC00668 and protein kinase N2 (PKN2). RNA pull-down assays validated the binding between HuR and LINC00668 (or PKN2). Moreover, either silencing of LINC00668 or HuR could decrease PKN2 mRNA stability or reduce PKN2 mRNA and protein levels. Furthermore, PKN2 expression was positively correlated with LINC00668 expression and HuR expression in GC tissues, and HuR expression was positively associated with LINC00668 expression in GC tissues. Finally, rescue assays confirmed that the suppressive effect of LINC00668 silencing on cell migration, invasion, and EMT process was reversed by PKN2 overexpression or HuR upregulation. In conclusion, LINC00668 cooperated with HuR-dependent upregulation of PKN2 to facilitate gastric cancer metastasis, which may provide a potential novel insight for GC treatment.
在中国，胃癌（GC）的发病率在所有恶性肿瘤中位居第一。由于高复发和远处转移，GC 导致了相当高的死亡率。长链非编码 RNA 长基因间非蛋白编码 RNA 668（LINC00668）已被报道在 GC 细胞中上调，并预测 GC 患者的预后不良。然而，LINC00668 在 GC 中的作用机制尚未得到充分研究。本研究旨在探讨 LINC00668 在 GC 中的作用。我们发现 LINC00668 水平在 GC 组织和细胞中上调，并预测预后不良。功能上，LINC00668 敲低抑制 GC 细胞迁移和侵袭。此外，LINC00668 敲低抑制上皮间质转化（EMT）过程。蛋白激酶 N2（PKN2）在 GC 细胞中发挥类似作用。LINC00668 敲低抑制肿瘤生长和转移。机制上，HuR 被预测与 LINC00668 和蛋白激酶 N2（PKN2）结合。RNA 下拉实验验证了 HuR 与 LINC00668（或 PKN2）的结合。此外，沉默 LINC00668 或 HuR 均可降低 PKN2 mRNA 的稳定性或减少 PKN2 mRNA 和蛋白水平。此外，GC 组织中 LINC00668 表达与 HuR 表达呈正相关，LINC00668 表达与 PKN2 表达呈正相关，GC 组织中 HuR 表达与 LINC00668 表达呈正相关。最后，挽救实验证实，PKN2 过表达或 HuR 上调逆转了 LINC00668 沉默对细胞迁移、侵袭和 EMT 过程的抑制作用。总之，LINC00668 与 HuR 依赖性 PKN2 上调合作促进胃癌转移，这可能为 GC 治疗提供新的潜在见解。
