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1.
PLoS Genet ; 19(2): e1010640, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36802400

RESUMEN

The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.


Asunto(s)
Neoplasias Gástricas , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/genética , Regulación hacia Abajo , Estrés Oxidativo , Proteína de Unión al GTP rac1/genética , Línea Celular Tumoral
2.
Oncogene ; 41(5): 732-744, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34845378

RESUMEN

Hyperactivation of RAS/MAPK signaling is commonly observed in hepatocellular carcinoma (HCC). Gain-of-function mutations of canonical RAS genes, however, are rarely detected and it remains unclear how the activity of this pathway is turned on during hepatocarcinogenesis. We performed a comprehensive analysis of RAS superfamily genetic alterations across ten subfamilies, 152 members in 377 HCC patients from the Cancer Genome Atlas database. RIT1 (Ras-like without CAAX 1) was the most frequently altered RAS member amplified in 13% of the HCC cohort. Both genomic amplification and CREB-mediated transcriptional activation contributed to the elevated RIT1 expression, and its overexpression correlated with RAS/MAPK activation and poor prognosis. Then, we found that RIT1-induced angiogenesis via the MEK/ERK/EIF4E/HIF1-α/VEGFA axis. MAP3K11 and MAP3K12, in addition to CRAF, could mediate this process by binding to RIT1. Moreover, RIT1 increased the phosphorylation of p38 MAPK and AKT to promote cell survival under reactive oxygen species stress. Based on this mechanistic understanding, we treated RIT1-overexpressing HCC with combined regimen sorafenib plus AKT inhibitor, and achieved enhanced antitumor effects in vivo. Our study reveals RAS "orphan" member RIT1 as the most common genetic alteration of RAS family in HCC and combination of sorafenib with AKT inhibitor might be a promising treatment strategy for RIT1-overexpressing HCC.


Asunto(s)
Carcinoma Hepatocelular , Humanos
3.
Cancer Res ; 81(4): 986-1000, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33310726

RESUMEN

The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient, which serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that calcium release-activated calcium modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, predominantly upregulated in the lymph node metastasis of gastric cancer, supports cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in gastric cancer tissues significantly correlated with poor differentiation, invasion, lymph node metastasis, and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation, and metastasis in both gastric cancer cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of gastric cancer cells by inducing FAK-mediated MAPK/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of gastric cancer. SIGNIFICANCE: These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway.


Asunto(s)
Adenocarcinoma/patología , Carcinogénesis/genética , Adhesiones Focales/metabolismo , Proteína ORAI2/fisiología , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Adhesiones Focales/genética , Adhesiones Focales/patología , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Proteína ORAI2/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
4.
Theranostics ; 10(25): 11535-11548, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33052231

RESUMEN

Objective: The transcription factor forkhead box protein O1 (FOXO1) is critical for regulating cytokine and chemokine secretion. However, its function in the tumor microenvironment (TME) remains largely unexplored. In this study, we characterized the prognostic value of FOXO1 and the interaction between tumor-derived FOXO1 and M2 macrophages in esophageal squamous cell carcinoma (ESCC). Methods: FOXO1 expression and macrophage infiltration in clinical samples and mouse models were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry staining. Western blotting, qRT-PCR, and enzyme-linked immunosorbent assay were used to evaluate chemokine ligand 20 (CCL20) and colony stimulating factor 1 (CSF-1) expression in FOXO1(+) and FOXO1(-) tumor cells. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and RNA sequencing. Transcriptional activity was measured using chromatin immunoprecipitation (ChIP)-qPCR. Tumor viability was investigated using XTT proliferation and foci formation assays. Results: FOXO1 upregulation in tumor tissues was found to drive the polarization of M0 macrophages and infiltration of M2 macrophages into the TME, resulting in worse prognosis in ESCC patients. CSF-1, a vital factor inducing M0-to-M2 polarization, was upregulated via a FOXO1-mediated mechanism. RNA sequencing results corroborated that the FOXO1-induced macrophages exhibited similar molecular signatures to the IL4-stimulated M2 macrophages. The transwell assays showed that FOXO1 promoted the migration of M2 macrophages via CCL20 secretion, which could be inhibited using an anti-CCL20 antibody. FOXO1(+) tumor-induced M2 macrophages promoted tumor proliferation via the FAK-PI3K-AKT pathway and the PI3K inhibitor could effectively impede the oncogenical process. Conclusions: FOXO1 facilitated M0-to-M2 polarization and the recruitment of M2 macrophages in the TME via the transcriptional modulation of CCL20 and CSF-1. Our data deciphered the FOXO1-dependent mechanism in M2 macrophage infiltration in the TME of ESCC, which has implications for the development of novel prognostic and therapeutic targets to optimize the current treatment against ESCC.


Asunto(s)
Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/inmunología , Proteína Forkhead Box O1/metabolismo , Regulación Neoplásica de la Expresión Génica/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Técnicas de Cocultivo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Esófago/patología , Femenino , Proteína Forkhead Box O1/genética , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Activación de Macrófagos , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Análisis de Matrices Tisulares , Macrófagos Asociados a Tumores , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Am J Cancer Res ; 9(11): 2331-2348, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31815038

RESUMEN

Gastric cancer is commonly diagnosed at an advanced stage when metastasis is almost inevitable. Despite numerous novel regulators have been identified in driving gastric cancer progression, much remains unclear due to the complex nature of cancer. Comparison of the transcriptome profiles of gastric primary tumor tissue, with its matched non-tumor and lymph node metastasis revealed frequent stepwise down-regulation of sclerostin domain containing 1 (SOSTDC1) related with tumor progression. Clinically, deficiency of this gene is associated with shortened survival of patients. Our results suggest that SOSTDC1 confers tumor-suppressive features in gastric cancer and silencing of it accelerates tumor growth and promotes the formation of lung metastasis. Although SOSTDC1 displayed limited inhibition of canonical SMAD-dependent bone morphogenetic proteins (BMP) pathway, it remarkably restrained the c-Jun activation and transcription of c-Jun downstream targets in the noncanonical BMP signaling pathway. Furthermore, c-Jun N-terminal kinase (JNK) blockage attenuated cell proliferative and migrative advantages of SOSTDC1 knockdown cell lines. Our study comprehensively elucidated the role of SOSTDC1 in gastric cancer progression and the results translate into potential therapy for gastric cancer.

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