Understanding the Role of NLRP7 in the Pathogenesis of Hydatidiform Mole
Assigned to: İlke Süder
Hydatidiform mole is the most prevalent gestational trophoblastic disease with trophoblast hyperproliferation and abnormal embryonal development. Familial biparental complete hydatidiform mole (FBCHM) has been thus far associated with either NLRP7 or KHDC3L mutations, both of which are maternal effect genes. Our lab has shown that NLRP7 deficiency predisposes iPSCs to trophoblast lineage commitment via BMP4 pathway upon inhibition of activin/Nodal and FGF signaling. Although NLRP7 seems to negatively regulate BMP4 signaling until trophoectoderm lineage commitment, how NLRP7 deficiency triggers trophoblast differentiation remained obscure. The obtained phenotype of no embryonic development and excessive mole tissues can be due to favoring trophoectoderm lineage over epiblast and primitive endoderm during early embryogenesis. Another hypothesis can be excessive trophoblast proliferation, which occupies uterus in a way to prevent embryo to be formed. Nevertheless, the HM phenotype can be due to the combination of trophoblast differentiation and hyperproliferation of these differentiated trophoblasts. Moreover, abnormal DNA methylation patterns can be cause or effect of trophoblast hyperproliferation/differentiation. Therefore, throughout the Ph.D. study, we are aiming at understanding (I) the mechanism leading to trophoectoderm lineage commitment on NLRP7-BMP4 axis, (II) the reason why DNA methylation patterns are abnormal in FBCHM and (III) the role of NLRP7 in trophoblast proliferation. Understanding the mechanism underlying the pathogenesis of HM may offer to elucidate preimplantation embryonic development and pave the way for therapies to prevent HM and other trophoblastic gestational diseases.
Elucidating the Putative Function of NLRP7 in Oncogenesis
Assigned to: Özen Kaya
The high expression level of NLRP7 has been associated with testicular seminoma, embryonal carcinoma and the progression of endometrial cancers. (Ohno, Kinoshita et al. 2008, Okada, Hirota, et al. 2004) In this Ph.D. thesis, we would like to answer the questions about how NLRP7 is involved in oncogenesis on the basis of testicular seminoma and endometrial cancer and which pathways contribute to NLRP7-driven cancer formation. From the beginning of the project, we showed that NLRP7 enhances tumor formation in vivo in SCID mice and possible interaction partners were determined through mass spectrometry analysis of HEC1A, an endometrial cancer cell line which was used for mouse xenograft tumor model. Physical interactions between candidate proteins linked to carcinogenesis and NLRP7 were verified by co-immunoprecipitation. Throughout the Ph.D. study, I would like to answer the questions listed below:
- What are the phenotypic characteristics of oncogenesis driven by NLRP7?
- Is NLRP7 driver or passenger in cancer formation?
- What are the mechanisms behind the functional outcomes of NLRP7 in oncogenesis?
- NLRP7 has a role in innate immune response, so how can tumor microenvironment be affected around NLRP7-driven endometrial cancer?
- Germ cell tumors seem to be affected by the aberrant presence of NLRP7 in the germ cells. Mostly epigenetic factors possibly have a function in the sustainment of pluripotency instead of differentiation to gonads and these factors have profound effects on the carcinogenesis in germ cells. Which factors may be affected by the upregulation of NLRP7 in germ cells?
The mechanisms including NLRP7 that give rise to carcinogenesis would be a very novel mechanism that has not been attributed to any pathogen recognition receptor before. Clarifying these mechanisms opens the way for the new drugs and NLRP7 can be used as a new prognosis marker for endometrial cancer and germ cell tumors.