Abstract
Purpose Plasmacytoma variant translocation 1 (PVT1) is a long noncoding RNA encoded by the human PVT1 gene, which has been verified to mediate tumorigenesis in gastric cancer. However, the underlying molecular mechanisms of PVT1 in gastric cancer (GC) remain largely unknown. Methods The tumorigenic ability of PVT1 was verified by subcutaneous and orthotopic mouse models. Flow cytometry assay and TdT-mediated dUTP Nick-End Labeling staining were conducted to explore the effects of PVT1 on gastric cancer cell apoptosis. We investigated the relative gene and protein that are involved in apoptosis in real-time PCR and western blot assay. The resistance to 5- Fluorouracil (5-Fu) caused by PVT1 was evaluated using cell viability assay. Then, to confirm the effects of PVT1 on 5-Fu resistance, we conducted the Kaplan-Meier analysis based on three public databases. Results We confirmed that PVT1 can promote the progression of gastric cancer. PVT1 inhibited the apoptosis of GC cells, which may account for its promotion on GC. We confirmed that PVT1 can regulate the expression of Bcl2 and enhance drug-resistance of gastric cancer to 5-Fu. Kaplan-Meier analysis showed that patients with high PVT1 expression do not experience survival related benefits from 5-Fu based chemotherapy; instead, therapy containing no 5-Fu chemotherapy can improve the first progression survival and overall survival of high PVT1 expression GC patients significantly. Conclusion Our results showed that PVT1 can inhibit the apoptosis and enhance the 5-Fu resistance of gastric cancer through the activation of Bcl2. PVT1 has the potential to serve as an indicator to predict 5-Fu treatment resistance.
Highlights
Gastric cancer (GC) is the second common cancer and the third most common cause of cancer death worldwide [1]
A growing amount of evidence indicates that long noncoding RNA (lncRNA) can play an important role in regulating the apoptosis in malignant tumors
It was reported that some lncRNAs are negative regulators of apoptosis in different types of cancer
Summary
Gastric cancer (GC) is the second common cancer and the third most common cause of cancer death worldwide [1]. New therapeutic methods are likely to derive from the improved understanding of the mechanisms of GC. The exploration of mechanisms of malignant tumors was mainly focused on protein-coding genes. The function of long noncoding RNA (lncRNA) in malignant tumors has attracted increasing attention. LncRNA is identified as the noncoding RNA, which is longer than 200 nucleotides and has limited protein-coding ability. Because of the lack of ability to encode protein, lncRNA was regarded as evolutionary “junk” or “transcriptional noise” in transcription at the beginning stage. With deepening of exploration, many crucial functionalities of lncRNA in physiological and pathological processes, such as chromatin modification, transcription, and posttranscriptional processing, were revealed. The dysregulation expressed with lncRNA has been demonstrated in multiple malignancies, which provides new insight into the cancer development
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