CSN1通过调控PARP1稳定性抑制食管鳞癌转移的机制及治疗意义

Esophageal squamous cell cancer (ESCC) is characterized by high incidence and mortality rate in China and the metastasis is the leading cause of death with mechanisms remains to be elucidated. Previously, we found that CSN1, the COP9 complex subunit, is downregulated in esophageal cancer tissues and predict better prognosis in esophageal cancer patients. CSN1 silencing results in increased proliferation, invasion and metastasis of esophageal squamous cells. Gene microarray and our subsequent verification revealed that knockdown of CSN1 significantly promotes the phosphorylation of STAT3. Furthermore, we found that CSN1 binds to the PARP1 protein and promotes PARP1 degradation. In addition, STAT3 signaling pathway is tightly involved in the metastasis of ESCC and PARP1 can promote the phosphorylation of STAT3. Combined with recent progresses and our data, we speculated that CSN1 could inhibit the phosphorylation of STAT3 by promoting PARP1 degradation, thereby inhibiting the metastasis of ESCC. Our project intends to validate this hypothesis in vitro and in vivo by applying a series of clinical and basic research experiments. We speculated that CSN1 could inhibit the metastasis of ESCC by targeting the PARP1/STAT3 axis, and it might provide new targets for the treatment of ESCC.

我国食管鳞癌发病率和死亡率均高，转移是其致死的主要原因。明确食管鳞癌转移调控机制将为研发相应靶向治疗策略，降低患者死亡率提供重要依据。本课题组前期研究发现敲低COP9复合物亚基CSN1能够促进食管鳞癌细胞增殖、侵袭和转移。基因芯片及后续验证表明，敲低CSN1显著促进STAT3通路的磷酸化。鉴于CSN1是蛋白酶体的组成部分，可调控泛素蛋白酶体降解过程，我们通过蛋白质谱分析筛选了与CSN1相互作用的蛋白，发现CSN1能够与PARP1蛋白结合，并促进PARP1降解。因STAT3是促进食管鳞癌转移的重要通路，而PARP1可以促进STAT3的磷酸化，我们推测：CSN1通过促进PARP1降解抑制STAT3磷酸化，进而抑制食管鳞癌转移。本项目拟通过临床及基础研究在体内外水平验证该假设，以期为阐明食管鳞癌转移机制及研发靶向治疗策略提供新思路。

肿瘤样本基因的异常表达被认为可能参与了肿瘤的发生和发展。明确CSN1在食管鳞癌中的表达、功能及调控机制对于研发相应的靶向治疗策略及改善患者预后意义重大。前期在线数据库结果表明，CSN1在食管癌临床组织中显著高表达，并且和TP53突变显著相关，这一现象PARP1也同样存在。临床组织样本中，我们也发现CSN1和PARP1在肿瘤组织中高表达，在配对正常组织中的差异表达还可能与某些消化酶、激素信号调控机制、细胞分化程度等多种因素相关，这一发现为揭示食管癌发生发展机制研究奠定了重要理论依据。此外，体外功能实验表明了CSN1的重要促癌作用，这可能与肿瘤血管生成及免疫调控密切相关。以上结果为食管癌的靶向治疗提供了重要基础。