RESUMEN
How and why distinct genetic alterations, such as BRCA1 mutation, promote tumorigenesis in certain tissues, but not others, remain an important issue in cancer research. The underlying mechanisms may reveal tissue-specific therapeutic vulnerabilities. Although the roles of BRCA1, such as DNA damage repair and stalled fork stabilization, obviously contribute to tumor suppression, these ubiquitously important functions cannot explain tissue-specific tumorigenesis by BRCA1 mutations. Recent advances in our understanding of the cancer genome and fundamental cellular processes on DNA, such as transcription and DNA replication, have provided new insights regarding BRCA1-associated tumorigenesis, suggesting that G-quadruplex (G4) plays a critical role. In this review, we summarize the importance of G4 structures in mutagenesis of the cancer genome and cell type-specific gene regulation, and discuss a recently revealed molecular mechanism of G4/base excision repair (BER)-mediated transcriptional activation. The latter adequately explains the correlation between the accumulation of unresolved transcriptional regulatory G4s and multi-level genomic alterations observed in BRCA1-associated tumors. In summary, tissue-specific tumorigenesis by BRCA1 deficiency can be explained by cell type-specific levels of transcriptional regulatory G4s and the role of BRCA1 in resolving it. This mechanism would provide an integrated understanding of the initiation and development of BRCA1-associated tumors.
Asunto(s)
Carcinogénesis , G-Cuádruplex , Neoplasias , Proteína BRCA1/genética , Carcinogénesis/genética , Daño del ADN , Reparación del ADN/genética , Replicación del ADN , Humanos , Neoplasias/genéticaRESUMEN
The fallopian tube (FT) is an important reproductive organ in females. The luminal epithelium of the FT is composed of highly polarized secretory and ciliated cells. Recently, accumulating lines of evidence have suggested that the origin of high-grade serous ovarian carcinoma (HGSC) is fallopian tube epithelial cells (FTECs). Due to the lack of a high-fidelity model for FTECs in vitro, homeostasis, differentiation, as well as the transformation of FTECs are still enigmatic. In this study, we optimized the culture condition for the stable expansion of basal stem cells, as well as inducing differentiation of basal cells into polarized secretory and ciliated cells in the air-liquid interface (ALI) condition suitable for long-term culture. This storable culture method of FTECs provides a versatile platform for studying differentiation mechanisms, intercellular communication, and transformation to HGSC, as well as the physiological function of the FT in vitro.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Células Epiteliales/citología , Epitelio/crecimiento & desarrollo , Trompas Uterinas/crecimiento & desarrollo , Células Madre/citología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Separación Celular , Criopreservación , Medios de Cultivo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Humanos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Cultivo Primario de Células , PorcinosRESUMEN
High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the development of the ovary. PAX2 expression is lost early in serous cancer progression, while PAX8 is expressed ubiquitously. These proteins are implicated in migration, invasion, proliferation, cell survival, stem cell maintenance, and tumor growth. Hence, targeting PAX2 and PAX8 represents a promising drug strategy that could inhibit these pro-tumorigenic effects. In this review, we examine the implications of PAX2 and PAX8 expression in the cell of origin of serous cancer and their potential efficacy as drug targets by summarizing their role in the molecular pathogenesis of ovarian cancer.