FOXD1-AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway.

Gastric cancer (GC) is a common gastrointestinal cancer with a high global mortality. Recent reports have suggested that long noncoding RNA (lncRNA) are implicated in multiple aspects of GC, including pathogenesis, progression, and therapeutic response. Herein, we investigated the function of FOXD1-AS1 in GC progression and chemoresistance. Expression of FOXD1-AS1 was low in normal stomach tissues but was upregulated in GC cell lines. Silencing of FOXD1-AS1 impaired GC cell proliferation and motility in vitro, and repressed tumor growth and metastasis in vivo. Importantly, FOXD1-AS1 upregulation increased the resistance of GC cells to cisplatin. Moreover, we found that FOXD1-AS1 promoted FOXD1 protein translation through the eIF4G-eIF4E-eIF4A translational complex. We also demonstrated that FOXD1-AS1 released eIF4E from phosphorylated 4E-BP1 and thereby strengthened the interaction of eIF4E with eIF4G by activating the PI3K/AKT/mTOR pathway. Activation of the PI3K/AKT/mTOR pathway was due to the post-transcriptional upregulation of PIK3CA, in turn induced by FOXD1-AS1-mediated sequestering of microRNA (miR)-466. Furthermore, we verified that FOXD1-AS1 facilitated GC progression and cisplatin resistance in a FOXD1-dependent manner. In conclusion, FOXD1-AS1 aggravates GC progression and chemoresistance by promoting FOXD1 translation via PIK3CA/PI3K/AKT/mTOR signaling. These findings highlight a novel target for treatment of patients GC, particularly patients with cisplatin resistance.

Wu Q ，Ma J ，Wei J ，Meng W ，Wang Y ，Shi M ... -  《-》

Long noncoding RNA OIP5-AS1 causes cisplatin resistance in osteosarcoma through inducing the LPAATβ/PI3K/AKT/mTOR signaling pathway by sponging the miR-340-5p.

The abnormal expression of long noncoding RNAs (lncRNAs) plays an important role in the regulation of human cancer progression and drug resistance. The lncRNA OPI5-AS1 is a crucial regulator in some cancers; however, its role in cisplatin resistance of osteosarcoma remains unclear. We found that OIP5-AS1 was significantly upregulated in cisplatin-resistant (CR) osteosarcoma cells MG63-CR and SaOS2-CR compared with the corresponding parental cells. OIP5-AS1 silencing suppressed cell growth in vitro and in vivo, and promoted apoptosis of MG63-CR and SaOS2-CR cells, indicating that knockdown of OIP5-AS1 significantly decreased cisplatin resistance in MG63-CR and SaOS2-CR cells. This conclusion was supported by the decreased expression of the drug resistance-related factors multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp) upon OIP5-AS1 silencing. In addition, OIP5-AS1 downregulation suppressed the PI3K/AKT/mTOR signaling pathway. Importantly, we demonstrated that OIP5-AS1 functions as a competing endogenous RNA of miR-340-5p and regulates the expression of lysophosphatidic acid acyltransferase (LPAATβ), which is a target of miR-340-5p. Moreover, downregulation of miR-340-5p partly reversed the inhibitory effect of OIP5-AS1 knockdown on the PI3K/AKT/mTOR pathway and therefore counteracted cisplatin resistance in MG63-CR and SaOS2-CR cells. In conclusion, OIP5-AS1 causes cisplatin resistance in osteosarcoma through inducing the LPAATβ/PI3K/AKT/mTOR signaling pathway by sponging the miR-340-5p. Our results contribute to a better understanding of the function and mechanism of OIP5-AS1 in osteosarcoma cisplatin resistance.

Song L ，Zhou Z ，Gan Y ，Li P ，Xu Y ，Zhang Z ，Luo F ，Xu J ，Zhou Q ，Dai F ... -  《-》

Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/β-catenin signaling pathways by up-regulating miR-34a.

HOX transcript antisense RNA (HOTAIR), a well-known long non-coding RNA (lncRNA), has been reported to be related to cisplatin (DDP) resistance in gastric cancers. However, the molecular mechanism of HOTAIR in DDP resistance of gastric cancer (GC) remains largely undefined. The aim of this study was to investigate the role and underlying mechanism of HOTAIR in regulating cisplatin resistance of GC. The results showed that HOTAIR was over-expressed in GC tissues and GC cell lines, while miR-34a was low-expressed. Luciferase reporter assay and RIP assay proved that HOTAIR directly bound to miR-34a. MiR-34a expression was significantly increased in si-HOTAIR-transfected cells. Anti-miR-34a reversed the effect of si-HOTAIR on the DDP resistance, apoptosis-related genes, PI3K/Akt and Wnt/β-catenin signaling pathways in DDP-resistant GC cells, indicating that the effects of HOTAIR are dependent on miR-34a. In addition, knockdown of HOTAIR enhanced DDP inhibitory effect on tumor growth in vivo. In conclusion, HOTAIR knockdown inhibited DDP resistance of gastric cancer cells by upregulating miR-34a. The effect of HOTAIR/miR-34a axis on GC cells may be involved in the PI3K/Akt and Wnt/β-catenin signaling pathways. The results indicated that HOTAIR might be a new potential target in GC therapy.

Cheng C ，Qin Y ，Zhi Q ，Wang J ，Qin C ... -  《-》

Long noncoding RNA TMPO-AS1/miR-126-5p/BRCC3 axis accelerates gastric cancer progression and angiogenesis via activating PI3K/Akt/mTOR pathway.

Gastric cancer (GC) is an aggressive tumor featured by uncontrolled cell proliferation and metastasis. In recent years, long noncoding RNAs (lncRNAs) act as crucial regulators and biological markers in multiple cancers. LncRNA TMPO-AS1 has been revealed to be an oncogene in some cancers. Nevertheless, there is little known about the biological role of TMPO-AS1 in GC. Reverse transcription-quantitative polymerase chain reaction analysis was used to examine the expression level of TMPO-AS1 in GC tissues and cells. Cell Counting Kit-8, colony formation, wound healing assays, and western blot analysis were performed to determine the role of TMPO-AS1 in GC cells. RNA pull-down, luciferase reporter, and RNA immunoprecipitation assays were used to test the interaction among TMPO-AS1, miR-126-5p, and BRCC3. TMPO-AS1 was highly expressed in GC tissues and cells. Upregulated TMPO-AS1 was closely associated with adverse prognosis of GC patients. Functional assays showed that TMPO-AS1 promoted GC cell proliferation, migration, and angiogenesis. Furthermore, it was found that TMPO-AS1 acted as a competing endogenous RNA for miR-126-5p to upregulate BRCC3 expression. Rescue assays revealed that TMPO-AS1 facilitated cellular progression of GC by sponging miR-126-5p and upregulating BRCC3. In addition, we found that the effects of the TMPO-AS1/miR-126-5p/BRCC3 axis on GC cell progression were related to the PI3K/Akt/mTOR pathway. Our study demonstrated that the TMPO-AS1/miR-126-5p/BRCC3 axis was involved in GC progression via the regulation of PI3K/Akt/mTOR pathway, which might provide a potential therapeutic strategy for GC.

Hu Y ，Zhang Y ，Ding M ，Xu R ... -  《-》

Downregulation of lncRNA ZEB1-AS1 Represses Cell Proliferation, Migration, and Invasion Through Mediating PI3K/AKT/mTOR Signaling by miR-342-3p/CUL4B Axis in Prostate Cancer.

Ma T ，Chen H ，Wang P ，Yang N ，Bao J ... -  《-》