背景:妊娠绒毛膜癌(GC)是一种高度恶性的滋养细胞肿瘤,通常由完全葡萄胎(HM)发展而来。NLRP7是导致复发性HM的主要基因,参与先天免疫反应,炎症和细胞凋亡。NLRP7可以在炎性小体依赖性或非依赖性途径中起作用。最近,我们已经证明NLRP7在GC肿瘤细胞中高表达,并有助于其肿瘤发生。然而,潜在的机制仍然未知。这里,我们研究了NLRP7在恶性(JEG-3)和非肿瘤(HTR8/SVneo)滋养细胞中控制这些过程的机制。细胞存活,去分化,伪装,比较了正常JEG-3细胞或NLRP7,JEG-3ShNLRP7敲低的侵袭性。此外,使用过表达NLRP7的HTR8/SVneo细胞来确定NLRP7过表达对非肿瘤细胞的影响。使用GC的转移性小鼠模型在体内进一步表征NLRP7参与肿瘤细胞生长和耐受性。
结果:我们证明了NLRP7(i)在HTR8/SVneo和JEG-3细胞中以炎症小体依赖性和非依赖性方式发挥作用,(ii)差异调节肿瘤细胞和非肿瘤细胞中NF-κB的活性;(iii)增加恶性细胞的存活率,去分化,和伪装;和(iv)促进肿瘤细胞在GC的临床前模型中肺的定殖。
结论:这项研究首次证明了NLRP7独立于其炎症小体机制的机制。有助于GC生长和肿瘤发生。NLRP7在这种罕见癌症中的临床相关性突出了其作为治疗耐药GC患者的分子靶标的潜在治疗前景。
Gestational choriocarcinoma (GC) is a highly malignant trophoblastic tumor that often develops from a complete hydatidiform mole (HM). NLRP7 is the major gene responsible for recurrent HM and is involved in the innate immune response, inflammation and apoptosis. NLRP7 can function in an inflammasome-dependent or -independent pathway. Recently, we have demonstrated that NLRP7 is highly expressed in GC tumor cells and contributes to their tumorigenesis. However, the underlying mechanisms are still unknown. Here, we investigated the mechanism by which NLRP7 controls these processes in malignant (JEG-3) and non-tumor (HTR8/SVneo) trophoblastic cells. Cell survival, dedifferentiation, camouflage, and aggressiveness were compared between normal JEG-3 cells or knockdown for NLRP7, JEG-3 Sh NLRP7. In addition, HTR8/SVneo cells overexpressing NLRP7 were used to determine the impact of NLRP7 overexpression on non-tumor cells. NLRP7 involvement in tumor cell growth and tolerance was further characterized in vivo using the metastatic mouse model of GC.
We demonstrate that NLRP7 (i) functions in an inflammasome-dependent and -independent manners in HTR8/SVneo and JEG-3 cells, respectively; (ii) differentially regulates the activity of NF-κB in tumor and non-tumor cells; (iii) increases malignant cell survival, dedifferentiation, and camouflage; and (iv) facilitates tumor cells colonization of the lungs in the preclinical model of GC.
This study demonstrates for the first time the mechanism by which NLRP7, independently of its inflammasome machinery, contributes to GC growth and tumorigenesis. The clinical relevance of NLRP7 in this rare cancer highlights its potential therapeutic promise as a molecular target to treat resistant GC patients.