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1.
J Cell Biol ; 223(2)2024 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-38095639

RESUMEN

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Neoplasias Colorrectales , Péptidos y Proteínas de Señalización Intracelular , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Colorrectales/genética , gamma Catenina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/metabolismo
2.
BMC Cancer ; 23(1): 1017, 2023 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-37867191

RESUMEN

BACKGROUND: The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS: This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS: Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS: In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos
4.
Future Oncol ; 19(15): 1029-1035, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37132469

RESUMEN

Advanced biliary tract cancer (BTC) has a poor prognosis, even after combined chemotherapy of gemcitabine and oxaliplatin (GEMOX). To investigate the efficacy and safety of GEMOX chemotherapy combining atezolizumab and bevacizumab in advanced BTC, the authors designed an open-label, single-arm, phase II clinical trial and will enroll patients with stage IV BTC. The participants will receive GEMOX chemotherapy combined with atezolizumab plus bevacizumab. The primary end point is objective response rate; the secondary end points are overall survival, disease control rate, progression-free survival, time to progression, duration of response and safety. The results of this trial are expected to provide novel, safe and effective treatment options for patients with advanced BTC, which could further improve their prognosis. Clinical Trial Registration: ChiCTR2100049830 (ChiCTR.org).


Asunto(s)
Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Gemcitabina , Oxaliplatino/uso terapéutico , Cisplatino/uso terapéutico , Bevacizumab/efectos adversos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
5.
Therap Adv Gastroenterol ; 16: 17562848231160630, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37007215

RESUMEN

Background: Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). Objectives: We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Design: Multicenter, single-arm, retrospective study. Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

6.
Cell Rep ; 42(4): 112340, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37027301

RESUMEN

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinogénesis/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , FN-kappa B/metabolismo , Ubiquitinación
7.
Front Immunol ; 14: 1107542, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36875125

RESUMEN

Background and aims: The efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients. Methods: This multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety. Results: Of 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths. Conclusions: IMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study. Clinical trial registration: http://www.chictr.org.cn, Identifier ChiCTR2200061793.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neutropenia , Radioterapia de Intensidad Modulada , Humanos , Bevacizumab , Estudios Prospectivos , Vena Porta
8.
Adv Sci (Weinh) ; 10(2): e2202448, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36453576

RESUMEN

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Ratones , Carcinoma Ductal Pancreático/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Guanosina Trifosfato , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína SOS1 , Neoplasias Pancreáticas
9.
Cell Death Differ ; 30(2): 383-396, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36396719

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we demonstrated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARγ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2a level at the NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provided a potential therapeutic strategy for NAFLD.


Asunto(s)
Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/metabolismo , Ratones Noqueados , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Dieta Alta en Grasa , Ubiquitinación , Ratones Endogámicos C57BL
10.
BMJ Open ; 12(12): e064688, 2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36521893

RESUMEN

INTRODUCTION: Vascular invasion and metastasis are poor prognostic factors in patients with hepatocellular carcinoma (HCC). The efficacy of available therapeutic regimens for unresectable HCC is not satisfactory in HCC with portal vein tumour thrombosis (PVTT). Therefore, this open-label, single-arm phase II clinical trial aims to investigate the efficacy and safety of radiotherapy combined with atezolizumab plus bevacizumab in treating HCC patients with PVTT. METHODS AND ANALYSIS: We plan to enrol patients diagnosed with unresectable HCC complicated by PVTT. Intensity-modulated radiotherapy (IMRT) combined with atezolizumab plus bevacizumab will be administered for treatment. Patients will initially receive radiotherapy, with each IMRT cycle lasting for 28 days and the total dose of tumour (DT) of 40 Gy/20 f/26 d. CT scan will be performed again, and the treatment plan will be reformulated after field constriction. The treatment will continue until the total DT is up to 54-56 Gy/27-28 f. The treatment with atezolizumab plus bevacizumab will be started at 3±1 days after the initiation of radiotherapy and will continue until unacceptable toxicity or disease progression. The primary endpoint is objective response rate (ORR), while the secondary endpoints include overall survival, disease control rate, progression-free survival, time to progression, duration of response and the rate of surgical conversions. Assuming an ORR of 47%, with a two-sided alpha error of 0.1, 90% power, and a 10% drop-out rate, the required number of evaluable patients is 42. ETHICS AND DISSEMINATION: This study will be conducted according to the standards of Good Clinical Practice and in compliance with the principles of the Declaration of Helsinki. The Ethics Committee of our Hospital has approved the protocol (EHBHKY2021-K-017). All participants are required to provide written informed consent. The results of the trial will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2100049831.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombosis de la Vena , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Vena Porta , Bevacizumab/efectos adversos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamiento farmacológico , Trombosis de la Vena/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
11.
Future Oncol ; 18(30): 3367-3375, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35968836

RESUMEN

The therapeutic effect of transcatheter arterial chemoembolization (TACE) is limited for patients with hepatocellular carcinoma (HCC). Herein, we designed an open-label, single-arm phase II clinical trial to investigate the efficacy and safety of TACE combined with atezolizumab plus bevacizumab for patients with Barcelona Clinic Liver Cancer (BCLC) stage-B HCC. Patients will initially receive TACE. Atezolizumab and bevacizumab will be initiated 2-14 days after the first TACE session. TACE will be repeated on demand. The primary endpoint is the objective response rate. The secondary end points include overall survival, disease control rate, progression-free survival, time-to-progression and safety. The study results will provide evidence for establishing a novel therapeutic regimen for patients with unresectable HCC. Clinical Trial Registration: ChiCTR2100049829 (ChiCTR.org).


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Ensayos Clínicos Fase II como Asunto , Neoplasias Hepáticas/terapia , Terapia Combinada/efectos adversos
12.
Oncogene ; 41(36): 4244-4256, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35906391

RESUMEN

Lung cancer is the most common malignancy and the leading cause of cancer death worldwide, and lung adenocarcinoma (LUAD) is the most prevalent subtype. Considering the emergence of resistance to therapies, it is urgent to develop more effective therapies to improve the prognosis. Here we reported that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) deficiency inhibited LUAD development both in vitro and in vivo. Mechanistically, PPDPF induces hyperactive STAT3 by interfering STAT3-PTPN1 interaction. Activated STAT3 promoted BMPR2 transcription, which further inhibited apoptosis. Moreover, PPDPF reduced NK cell infiltration and activation to develop an immunosuppressive microenvironment, which was also mediated by STAT3. Furthermore, we identified that the expression of PPDPF was positively correlated with the malignant features of LUAD, as well as BMPR2 and p-STAT3 level in clinical samples. Therefore, our study suggests that PPDPF positively regulates BMPR2 expression and facilitates immune escape via regulating STAT3 activity, providing a potential therapy target for LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/patología , Adenocarcinoma del Pulmón/patología , Apoptosis/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular , Células Asesinas Naturales/metabolismo , Neoplasias Pulmonares/patología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Microambiente Tumoral
13.
Cell Mol Gastroenterol Hepatol ; 14(1): 101-127, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35390516

RESUMEN

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. METHODS: The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. RESULTS: Our study has shown that ARID1A loss protected cells from glucose deprivation-induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. CONCLUSIONS: HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)-adenosine 5'-monophosphate-activated protein kinase (AMPK) axis.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Quinasas Activadas por AMP , Adenosina Monofosfato , Animales , Carcinoma Hepatocelular/patología , Proliferación Celular/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glucosa , Glutatión Transferasa , Humanos , Neoplasias Hepáticas/patología , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina Tiolesterasa/genética
14.
Toxins (Basel) ; 13(11)2021 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-34822586

RESUMEN

Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.


Asunto(s)
Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Ocratoxinas/toxicidad , Animales , Antígenos CD36/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Células Hep G2 , Hepatocitos/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , PPAR gamma/metabolismo
15.
Oncogene ; 40(34): 5302-5313, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34247189

RESUMEN

The prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory due to limited effective treatment options. In this work, we investigated the therapeutic efficacy of Terbinafine for HCC and the underlying mechanism. The influence of Terbinafine on cell growth, 3D spheroid formation, clonogenic survival, and protein synthesis was investigated in human HCC cell lines. Co-immunoprecipitation, immunofluorescence, and other techniques were employed to explore how Terbinafine exerts its anticancer effect. Subcutaneous tumorigenicity assay, orthotopic and patient-derived xenograft (PDX) HCC models were used to evaluate the anticancer effect of Terbinafine monotherapy and the combinatorial treatment with Terbinafine and sorafenib against HCC. The anticancer activity of Terbinafine was Squalene epoxidase (SQLE)-independent. Instead, Terbinafine robustly suppressed the proliferation of HCC cells by inhibiting mTORC1 signaling via activation of AMPK. Terbinafine alone or in combination with sorafenib delayed tumor progression and markedly prolonged the survival of tumor-bearing mice. The synergy between Terbinafine and sorafenib was due to concomitant inhibition of mTORC1 and induction of severe persistent DNA double-strand breaks (DSBs), which led to the delayed proliferation and accelerated cell death. Terbinafine showed promising anticancer efficacy in preclinical models of HCC and may serve as a potential therapeutic strategy for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Quinasas Activadas por AMP , Animales , Ratones , Terbinafina
16.
Nat Commun ; 12(1): 3059, 2021 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-34031390

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.


Asunto(s)
Hígado Graso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hígado/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proteínas Cullin/metabolismo , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo
17.
Aging (Albany NY) ; 13(7): 10672-10687, 2021 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-33839702

RESUMEN

Neuroepithelial cell transforming gene 1 (NET1), a member of the guanine nucleotide exchange factor family, is involved in various cancers, including gastric cancer, breast cancer and glioma. However, the role of NET1 in hepatocellular carcinoma (HCC) remains largely uncovered. In this study, we found that NET1 expression was upregulated in HCC, and that upregulated NET1 expression was closely associated with poor prognosis and some clinical characteristics in HCC patients. Whilst forced expression of NET1 in HCC cells was observed to significantly promote cell growth and metastasis in vitro and in vivo; downregulation of NET1 was shown to exhibit an opposite inhibitory effect. RNA-seq analysis and gene set enrichment analysis demonstrated that knockdown of NET1 significantly suppressed the level of Akt phosphorylation level and the expression of Akt downstream genes in HCC cells. Moreover, MK2206, a potent Akt inhibitor was shown to block the NET1-induced effects in HCC. Taken together, this study demonstrated that, through the Akt signaling pathway, NET1 plays an oncogenic role in HCC progression and metastasis. Hence, NET1 may potentially be used as a potential therapeutic target and prognostic marker of HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Metástasis de la Neoplasia/patología , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Proteínas Oncogénicas/genética , Fosforilación
18.
Proc Natl Acad Sci U S A ; 117(9): 4770-4780, 2020 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-32071245

RESUMEN

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial-mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Ensamble y Desensamble de Cromatina/fisiología , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Factores de Transcripción/metabolismo , Animales , Dedos de Zinc CYS2-HIS2 , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Noqueados , Mutación , Metástasis de la Neoplasia/patología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética
19.
Oncogene ; 38(48): 7281-7293, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31417183

RESUMEN

Bone morphogenetic protein 10 (BMP10), one member of the BMP family, is involved in various development events. Dysregulation of BMP10 has been observed in several diseases, including hypertensive cardiac hypertrophy, Hirschsprung disease and blood vessel formation. However, its role in liver cancer remains largely unknown. In this study, we reported that BMP10 was significantly downregulated in HCC at both mRNA and protein level. Decreased BMP10 was associated with bigger tumor size, worse TNM stage, earlier recurrence and poorer survival. BMP10 negatively regulated HCC cell proliferation in vitro and in vivo. Mechanism study revealed that BMP10 suppressed tumor cell growth by inhibiting STAT3 signaling. Interestingly, we found that cytoplasmic BMP10 interacted with both receptor protein tyrosine phosphatase sigma (PTPRS) and STAT3, which facilitated dephosphorylation of STAT3 by PTPRS. Altogether, our study has revealed the clinical significance of BMP10 in HCC, and suppression of HCC cell growth by BMP10 via PTPRS-STAT3 axis, providing a potential therapeutic strategy for targeting STAT3 signaling in HCC.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Factor de Transcripción STAT3/metabolismo , Adulto , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proteínas Morfogenéticas Óseas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Fosforilación , Pronóstico , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Nat Commun ; 10(1): 2510, 2019 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-31175290

RESUMEN

Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis-promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Primarias Múltiples/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundario , Células HEK293 , Humanos , Receptores de Hialuranos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Mucinas/metabolismo , Invasividad Neoplásica , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Trasplante de Neoplasias , Neoplasias Primarias Múltiples/patología , ARN Mensajero/metabolismo , Carga Tumoral
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