缺氧微环境下RHBDL2与N1ICD相互作用激活Notch信号通路促进胰腺癌细胞侵袭转移

High invasion and metastasis of pancreatic cancer is one of the important reasons for its poor prognosis. Current studies confirmed that the hypoxic microenvironment of solid tumors is an important predisposing factor for its high invasiveness and metastasis, and its molecular mechanism is not clear at present. However, the hypoxic microenvironment activates the Notch signaling pathway, leading to enhanced invasion and metastasis of tumor cells. The applicant's study found previously: ①RHBDL2 was highly expressed and significantly associated with lymph node and distant metastasis and overall survival in pancreatic cancer. ②The expression of RHBDL2 was positively correlated with hypoxia-related protein (HIF-1α, HIF-1α, etc.) under hypoxic microenvironment. ③ Public databases and protein mass spectrometry found that RHBDL2 may interact with N1ICD ,then activate the Notch signaling pathway. Therefore, we hypothesized that the hypoxic microenvironment can promote the interaction between RHBDL2 and N1ICD ,then activate the Notch pathway to promote the invasion and metastasis of pancreatic cancer cells. This study will further explore the molecular mechanisms underlying the interaction of RHBDL2 and N1ICD in the hypoxic microenvironment and further activate the Notch signaling pathway to promote the invasion and metastasis of pancreatic cancer cells, providing new molecular targets and diagnostic markers for the treatment and prognosis of pancreatic cancer.

胰腺癌高侵袭转移性是其预后极差的重要原因之一，现研究证实缺氧微环境是其高侵袭转移性的重要诱发因素，然而其分子机制目前尚不明确，而缺氧微环境又可激活Notch信号通路，导致肿瘤细胞的侵袭转移能力增强。申请人前期研究发现：①RHBDL2在胰腺癌中高表达，与胰腺癌淋巴结及远处转移、患者总生存率显著相关；②RHBDL2与缺氧相关蛋白（HIF-1α、HIF-1α等）表达呈正相关，并在缺氧微环境下促进胰腺癌细胞的侵袭转移；③公共数据库及蛋白质谱实验分析发现RHBDL2可能与N1ICD相互作用并激活Notch信号通路。因此提出研究假设：缺氧微环境可促进RHBDL2与N1ICD相互作用，激活Notch通路从而增强胰腺癌细胞的侵袭转移能力。本研究将深入探索缺氧微环境下RHBDL2与N1ICD相互作用激活Notch信号通路促进胰腺癌细胞侵袭转移作用的分子机制，为胰腺癌的治疗和预后提供新的分子靶点及诊断标记。

胰腺癌是恶性程度最高的癌症之一，其特点是转移早，化疗效果有限，并且预后不良。因此，探索新的胰腺癌的治疗策略很重要。RHBDL2在宫颈癌和乳腺癌中有差异表达。然而，RHBDL2在胰腺癌中的表达尚不清楚。我们发现RHBDL2在人胰腺癌细胞和组织中高度表达，并且与远处转移和胰腺癌患者生存率差相关。功能获得实验和功能缺失实验结果表明，RHBDL2能促进人胰腺癌细胞在体内外的增殖和迁移。RNA-Seq结果提示RHBDL2可能参与Notch信号通路的激活。IMR-1可恢复RHBDL2导致的胰腺癌细胞的增殖和转移能力。RHBDL2与Notch1相互作用并裂解Notch1，释放N1ICD。RHBDL2降低了N1ICD的泛素化水平并与去泛素化酶OTUD7B合作，通过泛素-蛋白酶体途径稳定N1ICD的表达。RHBDL2通过OTUD7B稳定N1ICD并激活Notch通路促进胰腺癌细胞增殖和迁移。因此，这可能是一种潜在的胰腺癌治疗策略。