HoxC11通过SphK1转录成瘾性调节非小细胞肺腺癌中核IKKα介导的炎症微环境研究

Lung cancer is the leading cause of morbidity and mortality in China, 20% of lung cancer is related to inflammation, but its mechanism remains less known. The regulation of gene expression plays an important role in the malignant transformation of nonresolving inflammation. Our previous findings showed that transcription factor HoxC11 bound to sphingosine kinase (SphK1) that was consistently expressed in non small cell lung cancer(NSCLC), and IKKalpha was found to be localized in the nucleus as a chromatin modifier. We also established that the transplanted tumor, patient-derived xenograft (PDX) and conditional knockout mice and lung cancer samples library. We will set HoxC11, SphK1 and IKKalpha as a key net node, and we will explore whether and how IKKalpha regulates SphK1 expression, and SphK1 increases S1P concentrations in the cytoplasm, in turn, S1P promotes translocalization of IKKalpha from the nucleus into the cytoplasm after IKKalpha disassociates from the intact complex of IKKalpha and STAT3 in the nucleus that directly represses inflammatory factors. Furthermore, activation of STAT3 increases expression of inflammatory cytokines and promotes malignant transformation of inflammatory microenvironment. Through this project,we will establish a novel signaling network regulated by HoxC11 in inflammatory microenvironment of non-small cell lung adenocarcinoma. We also propose new evidence about targeting transcription factors and metabolites antagonistic to the malignant transformation of nonresolving inflammation from a new perspective that provide a new idea for the treatment of tumor inflammatory microenvironment.

我国肺癌为发病率、死亡率双率第一，20%的肺癌与炎症相关。在肿瘤微环境中，肿瘤细胞和多种炎症细胞/因子形成复杂的动态调控网络和非可控炎症状态，促进肿瘤恶性转化，然其主要机制和关键节点不清楚。申请者前期发现转录因子HoxC11在非小细胞肺癌（NSCLC）中持续表达且靶向鞘氨醇激酶SphK1，关键信号分子IKKα定位于细胞核内。本项目拟以HoxC11、SphK1和IKKα为信号调控网络的关键节点，采用已有的肺癌移植瘤、PDX、自发肺癌和肺组织诱导性基因敲除鼠，探讨HoxC11直接上调SphK1/S1P并促进IKKα出核，促进STAT3活化而直接上调炎症因子表达，导致炎症微环境恶性转化，从而揭示调控肿瘤/炎症微环境的新机制。通过本项目的研究，将明确HoxC11转录成瘾性调节调控NSCLC的新途径，提出靶向抑制HoxC11和磷脂代谢产物S1P而拮抗炎症恶性转化的证据，为NSCLC治疗提供新思路。

肺癌是我国肿瘤患者死亡的首要原因，同时也是发病率最高的肿瘤。其中肺腺癌是肺癌最常见的类型，其发病机制尚不明确，现存治疗方式也疗效有限。晚期肺腺癌患者多应用EGFR抑制剂等靶向药物，但大多数患者常在用药一年后出现肿瘤耐药。新的发病和耐药机制，以及更有效的治疗方式仍有待进一步探索。转录因子HOXC11被报道与胚胎期后肢和后肾发育相关，其在肿瘤中的作用也逐渐被认识。HOXC11属于HOX家族第三簇基因，编码的HOXC11蛋白可以作为转录因子来影响下游多个靶基因的表达。我们的研究发现HOXC11在肺腺癌中高表达，并与患者较差的总生存期相关。HOXC11可以增强肺腺癌细胞的增殖、迁移、侵袭、克隆形成能力及细胞周期的进展，同时也加速了裸鼠皮下移植瘤和肺转移瘤的形成。相反，在LUAD细胞中，HOXC11的缺失显著抑制了这些恶性表型。同时，HOXC11可以通过直接结合SPHK1的启动子区来调控其表达。HOXC11通过促进SPHK1的表达影响肺腺癌的发生发展。此外，HOXC11在肺癌中的表达受到NF-κB信号通路中的关键激酶IKKα的调控，其机制与HOXC11的泛素化有关。而USP8虽然与HOXC11不存在直接结合，但USP8的表达可以稳定HOXC11水平。在肺腺癌中直接干预HOXC11的表达或促进其通过蛋白酶体途径降解，或抑制HOXC11的下游靶基因SPHK1的表达，可以作为肺腺癌的潜在治疗靶点。与此同时，HOXC11也是预测肺腺癌患者预后的一个有效生物标志物。