lncRNAs在结外鼻型NK/T细胞淋巴瘤复发转移中的功能机制与预后价值研究

Many clinical studies showed a favorable survival outcome for early stage Extranodal nasal-type NK/T-cell lymphoma (NKTCL) by using primary radiotherapy and chemotherapy. But still 20~30% of patients endured relapse or progression after or during initial treatment. Distant failure was the primary failure pattern. lncRNA plays a role in prognosis of NKTCL have not been elaborated. In order to explore the involvement of lncRNAs in relapse and metastasis of NKTCL, lncRNA array was carried out to compare the expression differences of lncRNAs in tumor tissues between two groups of NKTCL patients with favorable (long term disease-free survival) and unfavorable prognosis (distant failure). The data show that 25 lncRNAs were differentially altered in response to distant failure. Based on this finding, we next plan to further identify lncRNAs correlated with relapse and metastasis of NKTCL, recover the cellular function and mechanism of these lncRNAs, finally evaluate their prognostic value. Our main strategy is using qPCR, RNAscope technology, Kaplan-Meier survival analysis to validate prognosis-associated lncRNAs. Next we will reveal the cellular function regulated by these lncRNAs, including proliferation, migration and invasion, radiosensitivity and chemosensitivity. The lncRNA signaling may be discovered and confirmed by mRNA array and lncRNA/mRNA coexpression analysis, RNA pull down and MS, CHIP, CHIRP et al. Survival analysis using multivariate Cox regression was performed to observe the impact of the lncRNAs and other clinical factors on NKTCL outcome. Through all the above efforts, we might find a new regulation mechanism of NKTCL metastasis and highlight the potential of lncRNAs as a prognosis predictor for precision cancer therapy. The results of this study are expected to improve the prognostic model, and guide precision therapy in the clinic.

基于早期结外鼻型NK/T细胞淋巴瘤（NKTCL）治疗后20-30%的病人出现远处转移，是导致治疗失败主要原因的临床现状，本课题组前期利用lncRNA和mRNA芯片筛选与NKTCL复发转移相关的差异表达lncRNAs和mRNAs。在此重要线索基础上，本项目拟在国际上首次进一步鉴定参与NKTCL复发转移的关键lncRNAs，研究其在复发转移过程中的功能和作用机制，以及作为预后指标的可能性。主要策略是利用qPCR、RNAscope原位杂交、K-M生存分析等方法明确与NKTCL复发转移相关的lncRNAs；通过细胞学实验证实lncRNAs在NKTCL生长、转移和放化疗敏感性中的功能；利用lncRNA芯片-mRNA芯片整合分析、RNA pull down和质谱等技术，探索lncRNAs的分子作用机制；采用多因素分析，建立、完善并验证lncRNA临床-生物预后模型，从而指导临床精准治疗，提高患者生存。

基于早期结外鼻型NK/T细胞淋巴瘤（NKTCL）治疗后20-30%的病人出现远处转移，是导致治疗失败主要原因的临床现状，本课题组前期利用lncRNA和mRNA芯片筛选与NKTCL复发转移相关的差异表达lncRNAs和mRNAs。在此基础上，本课题利用qPCR、RNAscope原位杂交、K-M生存分析等方法明确3个与NKTCL复发转移显著相关的lncRNAs，ENST00000509416.1，ENST00000565979.1，TCONS_00007354，通过细胞学实验证实了lncRNAs在NKTCL发生发展中的作用；利用lncRNA芯片-mRNA芯片整合分析技术，探索lncRNAs的分子作用机制。同时扩大样本量验证，通过生信分析建立了基于lncRNAs，miRNAs, mRNAs的生物预后分型。在建立生物预后模型的同时，进一步对NK/T细胞淋巴瘤的临床数据库进行分析，完善临床预后模型，证实了PFS24可以做为OS的替代指标用于研究设计与预后分层；同时证实了无论是在哪个分期和风险分层下，非阿霉素方案均显著提高阿霉素方案的患者疗效；进一步指导临床随诊，试验设计与治疗。