核仁小RNA-SNORA21促进自噬在诱导胆囊癌失巢凋亡抵抗中的调控机制和干预策略研究

Gallbladder cancer has an extremely poor prognosis with metastasis at early stage. Till now there is still no effective way to prevent and treat metastasis of gallbladder cancer. Anoikis resistance is a vital step during cancer progression and metastatic colonization, and it is of great significance to repress anoikis resistance in order to suppress metastasis and improve prognosis in gallbladder cancer. snoRNAs belong to the non-coding RNA family. snoRNAs are important regulatory molecules involved in tumorigenesis. In our previous research, snoRNA chip confirmed an enhanced level of SNORA21 in gallbladder cancer tissues. We also found that the blockage of SNORA21 inhibited autophagy and anoikis resistance. Under condition of detachment-induced anoikis, autophagy serves as an important cytoprotective function that promotes metastatic cells survival. We then propose scientific hypothesis that SNORA21 may enhance autophagy and induce anoikis resistance. The aim of the study is to use bioinformatic analysis to investigate SNORA21 related gene function and pathway; further in vitro and in vivo experiments focusing on intervention on autophagy induced by SNORA21. The current study may elucidate the new mechanism of autophagy induced by SNORA21 in anoikis resistance and provide a potential strategy for target therapy of metastasis of gallbladder cancer.

胆囊癌易转移预后差，目前尚无有效防治措施。失巢凋亡抵抗是肿瘤细胞转移潜能的重要标志，阻遏肿瘤细胞失巢凋亡抵抗对改善预后意义重大。snoRNA是一类非编码RNA，既往研究证实其在肿瘤发生发展过程中具有重要调控地位。我们前期通过snoRNA表达谱等技术研究发现：胆囊癌组织中snoRNA-SNORA21表达显著升高；干扰其表达后，胆囊癌细胞自噬水平及失巢凋亡抵抗能力均显著降低。肿瘤细胞处于失巢状态时，自噬的激活有助于其抵抗失巢凋亡，更进一步促进肿瘤转移。据此提出科学假说：SNORA21可能通过激活自噬进而诱导胆囊癌细胞失巢凋亡抵抗。本研究拟通过生物信息学方法锚定SNORA21相关基因及其功能富集相关通路；通过靶向干预SNORA21-自噬环节，探索SNORA21调控胆囊癌细胞失巢凋亡抵抗的作用机制，为阐明胆囊癌转移机制挖掘全新研究方向，并为临床防治胆囊癌转移提供潜在药靶。

胆囊癌易转移预后差，目前尚无有效防治措施。失巢凋亡抵抗是肿瘤细胞转移潜能的重要标志，阻遏肿瘤细胞失巢凋亡抵抗对改善预后意义重大。snoRNA是一类非编码RNA，既往研究证实其在肿瘤发生发展过程中具有重要调控地位。我们前期研究发现：胆囊癌组织中snoRNA-SNORA21表达显著升高；干扰其表达后，胆囊癌细胞自噬水平及失巢凋亡抵抗能力均显著降低。肿瘤细胞处于失巢状态时，自噬的激活有助于其抵抗失巢凋亡，更进一步促进肿瘤转移。后续研究我们通过生物信息学方法锚定SNORA21相关基因及其功能富集相关通路；通过靶向干预SNORA21-自噬环节，发现SNORA21通过激活自噬进而诱导胆囊癌细胞失巢凋亡抵抗，为阐明胆囊癌转移机制挖掘全新研究方向，并为临床防治胆囊癌转移提供潜在药靶。