RESUMO
The Rab small GTPases are characterized by the distinct intracellular localization and modulate various endocytic, transcytic and exocytic transport pathways. Rab proteins function as scaffolds that connect signaling pathways and intracellular membrane trafficking processes through the recruitment of effectors, such as tethering factors, phosphatases, motors and kinases. In different cancers, Rabs play as either an onco-protein or a tumor suppressor role, highly dependending on the context. The molecular mechanistic research has revealed that Rab proteins are involved in cancer progression through influences on migration, invasion, metabolism, exosome secretion, autophagy, and drug resistance of cancer cells. Therefore, targeting Rab GTPases to recover the dysregulated vesicle transport systems may provide potential strategy to restrain cancer progression. In this review, we discuss the regulation of Rab protein level and activity in modulating pathways involved in tumor progression, and propose that Rab proteins may serve as a prognostic factor in different cancers.
Assuntos
Neoplasias , Proteínas rab de Ligação ao GTP , Humanos , Proteínas rab de Ligação ao GTP/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/enzimologia , Transdução de Sinais , Animais , Autofagia/fisiologiaRESUMO
Genes encoding subunits of SWI/SNF (BAF) chromatinremodeling complexes are recurrently mutated in a broad array of tumor types, and among the subunits, ARID1A is the most frequent target with mutations. In the present study, it was reported that ARID1A inhibits the epithelialmesenchymal transition (EMT) and stemness of ovarian cancer cells, accompanied by reduced cell viability, migration and colony formation, suggesting that ARID1A acts as a tumor suppressor in ovarian cancer. Mechanistically, ARID1A exerts its inhibitory effects on ovarian cancer cells by activating the Hippo signaling pathway. Conversely, the overexpression of a gainoffunction transcriptional coactivator with PDZbinding motif (TAZ) mutant (TAZSer89) effectively reverses the effects induced by ARID1A. In addition, activation of Hippo signaling apparently upregulates ARID1A protein expression, whereas ectopic expression of TAZSer89 results in the markedly decreased ARID1A levels, indicating a feedback of ARID1ATAZ in regulating ovarian cancer cell EMT and stemness. Thus, the present study uncovered the role of ARID1A through the Hippo/TAZ pathway in modulating EMT and stemness of ovarian cancer cells, and providing with evidence that TAZ inhibitors could effectively prevent initiation and metastasis of ovarian cancer cases where ARID1A is lost or mutated.
Assuntos
Proteínas de Ligação a DNA , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Linhagem Celular Tumoral , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Movimento Celular , Proliferação de Células , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genéticaRESUMO
As the fifth most common cancer in the world, gastric cancer (GC) ranks as the third major cause of cancer-related death globally. Although surgical resection and chemotherapy still remains the mainstay of potentially curative treatment for GC, chemotherapy resistance and adverse side effects limit their clinical applications. Thus, further investigation of the mechanisms of carcinogenesis in GC and discovery of novel biomarkers is of great concern. We herein report that the elevated expression of GPR137 is correlated with GC. Overexpression of GPR137 potentiates human gastric cancer AGS cell malignancy, including proliferation, migration, invasion, colony formation and xenograft growth in nude mice in vivo, whereas knockout of GPR137 by CRISPR/Cas9 gene editing exerts the opposite effects. Mechanistically, GPR137 could bind to MST, the upstream kinases in Hippo pathway, which disrupts the association of MST with LATS, subsequently activating the transcriptional co-activators, YAP and TAZ, and thereby triggering the target transcription and the alterations in GC cell biological actions consequently. Therefore, our findings may provide with the evidence of developing a potentially novel treatment method with specific target for GC.