Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

Abstract

Background/Aims: The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. Methods: The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial–mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. Results: XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. Conclusion: High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells.

LncRNA NEAT1 promotes gastric cancer progression via miR-1294/AKT1 axis

“…Recently, dysregulated lncRNAs have been presented to be implicated in the malignant progression of GC via affecting the PI3K/AKT/mTOR signaling pathway [39]. For example, lncRNA LOC101928316 facilitated the development of GC by modulating the PI3K/AKT/mTOR signaling pathway [12]; MALAT1/miR-183/SIRT1 axis contributed to the regulation of GC via PI3K/AKT/ mTOR pathway [13] and lncRNA XLOC_006753 could induce cell proliferation, cell cycle, and metastasis but inhibit apoptosis in multidrug-resistant GC cells through promoting the PI3K/AKT/mTOR pathway [33]. NEAT1 has reported to activate the PI3K/AKT pathway to facilitate GC cell viability and migration [27].…”

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…Similarly, long non-coding RNAs also play an important role in drug resistance. The development of MDR is promoted by high expression of XLOC_006753, and its development is activated by the PI3K/AKT/mTOR signaling pathway in GC cells 82 . LncRNA-HOTAIR silencing significantly reduced the phosphorylation of PI3K, which suggests that knocking down lncRNA-HOTAIR effectively reduced the resistance of breast cancer cells to DOX via inhibition of the PI3K/ AKT/mTOR signaling pathway 83 .…”

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

“…MiRNAs and lncRNAs play a vital role in regulating gene expression via their fine regulation at various levels, including transcription, translation and protein functions. Multiple miRNAs and lncRNAs not only can serve as biomarkers for diagnosis of multiple cancers, but also are involved in drug resistance [19][20][21][22][23][24][25][26]. Lots of ncRNAs have been found to be abnormally expressed in HCC and to be associated with the invasion, metastasis, drug resistance and radioresistance of HCC cells [19][20][21][22][23][24][25][26].…”