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. 2018 Feb 14;9(2):235.
doi: 10.1038/s41419-018-0265-y.

Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma

Yi He  1   2   3 , Yizhou Jing  2 , Fang Wei  2 , Yanyan Tang  1   2 , Liting Yang  2 , Jia Luo  1 , Pei Yang  1 , Qianxi Ni  1 , Jinmeng Pang  1 , Qianjin Liao  1 , Fang Xiong  3 , Can Guo  2 , Bo Xiang  2 , Xiaoling Li  1   2   3 , Ming Zhou  2   3   4 , Yong Li  2   5 , Wei Xiong  1   2   3 , Zhaoyang Zeng  6   7   8 , Guiyuan Li  9   10   11
Affiliations

Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma

Yi He et al. Cell Death Dis. .

Abstract

The long non-coding RNA, plasmacytoma variant translocation 1 (PVT1), is highly expressed in a variety of tumors, and is believed to be a potential oncogene. However, the role and mechanism of action of PVT1 in the carcinogenesis and progression of nasopharyngeal carcinomas (NPCs) remains unclear. In this study, for the first time, we have discovered that PVT1 shows higher expression in NPCs than in normal nasopharyngeal epithelial tissue, and patients with NPCs who show higher expression of PVT1 have worse progression-free and overall survivals. Additionally, we observed that the proliferation of NPC cells decreased, and their rate of apoptosis increased; these results indicated that the knockdown of PVT1 expression in the NPC cells induced radiosensitivity. Further, we have shown that the knockdown of PVT1 expression can induce apoptosis in the NPC cells by influencing the DNA damage repair pathway after radiotherapy. In general, our study shows that PVT1 may be a novel biomarker for prognosis and a new target for the treatment of NPCs. Additionally, targeting PVT1 may be a potential strategy for the clinical management of NPC and for the improvement of the curative effect of radiation in NPCs.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. PVT1 is upregulated in NPC tissues and that is associated with poor prognosis.
PVT1 was upregulated in the Gene Expression Profiling (GEP) datasets a GSE64634, b GSE12452, and c GSE53819, **P < 0.01, ***P < 0.001. d Representative images of the detection of the expression of PVT1 in NPC tissues and adjacent non-tumor NPE tissues by in situ hybridization. Upper panel: magnification = ×200, scale bars = 50 μm; lower panel: magnification = ×400, scale bars = 20 μm. e The expression of PVT1 in NPC tissues (n = 94) is higher than in non-tumor NPE tissues (n = 33). f The expression levels of PVT1 in the radioresistant and radiosensitive NPC tissues. Treatment data could not be obtained for two patients. Kaplan–Meier survival curves of NPC patients show that NPC patients with high expression of PVT1 (n = 60) have shorter g RFS and h OS than patients with low expression of PVT1 (n = 34)
Fig. 2
Fig. 2. PVT1 knockdown enhances radiosensitivity in NPC cells.
a Compared to a scrambled RNA sequence (used as negative control (NC)), the siRNA specifically targeting PVT1 (siPVT1) significantly inhibits PVT1 expression in the NPC cell lines CNE2 and 5-8F. b Clone formation assay shows that PVT1 knockdown induces radiosensitivity in NPC cells. CNE2 and 5-8F cells were transfected by scrambled RNA (NC) or siRNA targeting PVT1 (siPVT1), and irradiated with 2–8 Gy of radiation; 12 days later the cells were stained (left panel) and dose survival curves were constructed using linear quadratic model analysis (right panel). c Proliferation of NPC cells following radiotherapy. In the NPC cell lines 5-8F and CNE2, PVT1 knockdown via siRNA treatment and irradiation with a dose of 6 Gy radiation shows sustained growth inhibition, although PVT1 knockdown alone does not reduce the proliferation of these cells. *P < 0.05; **P < 0.01; ***P < 0.001; ns, no significance.
Fig. 3
Fig. 3. PVT1 knockdown promotes apoptosis in NPC cells after radiotherapy.
CNE2 and 5-8F cells were transfected by either scrambled RNA (NC) or siRNA targeting PVT1 (siPVT1), and irradiated with a dose of 6 Gy and 4Gy X-radiation, respectively. Apoptosis in NPC cells was detected by flow cytometry. In NPC cells, PVT1 knockdown promotes apoptosis induced by radiotherapy, although PVT1 knockdown alone did not significantly induce apoptosis. **P < 0.01
Fig. 4
Fig. 4. Knockdown of PVT1 can attenuate the ability of DNA repair in NPC cells after radiotherapy.
NPC cell lines 5-8F and CNE2 were transfected by either scrambled RNA (NC) or siRNA that targeted PVT1 (siPVT1), and irradiated with a dose of 8 Gy X-radiation. The activation of key proteins, ATM, p53, and Chk2, in the DNA repair pathway was detected by western blot analysis by measuring their phosphorylation levels (p-ATM, p-p53, p-Chk2). Knockdown of PVT1 significantly reduced the phosphorylation levels of these proteins after radiotherapy. GAPDH was used as an internal control.
Fig. 5
Fig. 5. Knockdown of PVT1 activates caspases and PARP after radiotherapy.
NPC cell lines 5-8F and CNE2 were transfected by either scrambled RNA (NC) or siRNA that targeted PVT1 (siPVT1), and irradiated with a dose of 6 Gy X-radiation. The activation of caspase-7, caspase-9, and PARP was detected by western blot analysis. PVT1 knockdown significantly increased the cleavage of caspase-7, caspase-9, and PARP. GAPDH was used as an internal control.
Fig. 6
Fig. 6
The mechanism of action of PVT1 in the resistance to radiotherapy in nasopharyngeal carcinoma
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