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1.
J Transl Med ; 20(1): 579, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36494846

RESUMO

Primary liver cancer (PLC) is a common gastrointestinal malignancy worldwide. While hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two major pathologic types of PLC, combined HCC and ICC (cHCC-ICC) is a relatively rare subtype that shares both hepatocyte and cholangiocyte differentiation. However, the molecular feature of this unique tumor remains elusive because of its low incidence and lack of a suitable animal model. Herein, we generated a novel spontaneous cHCC-ICC model using a Sleeping Beauty-dependent transposon plasmid co-expressing oncogenic Myc and AKT1 and a CRISPR-Cas9 plasmid expressing single-guide RNA targeting p53 into mouse hepatocytes via in situ electroporation. The histological and transcriptional analysis confirmed that this model exhibits cHCC-ICC features and activates pathways committing cHCC-ICC formation, such as TGF-ß, WNT, and NF-κB. Using this model, we further screened and identified LAMB1, a protein involved in cell adhesion and migration, as a potential therapeutic target for cHCC-ICC. In conclusion, our work presents a novel genetic cHCC-ICC model and provides new insights into cHCC-ICC.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Modelos Animais de Doenças , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Estudos Retrospectivos
2.
J Transl Med ; 19(1): 347, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389031

RESUMO

BACKGROUND: Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM. METHODS: TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages. RESULTS: We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages. CONCLUSIONS: Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Linhagem Celular Tumoral , Humanos , Ferro , Camundongos , Macrófagos Associados a Tumor
3.
Ann Surg Oncol ; 27(5): 1546-1557, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157528

RESUMO

BACKGROUND: The mechanistic target of rapamycin (mTOR) pathway, containing mTOR complex 1 (mTORC1) and mTORC2, is dysregulated in multiple cancers, including hepatocellular carcinoma (HCC). Mammalian lethal with sec-13 protein 8 (mLST8) is a shared constituent of both mTORC1 and mTORC2, yet little is known regarding its role in HCC development. METHODS: mLST8 expression was detected in a total of 186 pairs of HCC and adjacent non-tumor specimens. The correlation between mLST8 level and clinicopathological features or prognostic significance were analyzed. The role of mLST8 on biological functions was also preliminarily studied. RESULTS: The study revealed that the mLST8 level was dramatically higher in HCC specimens than in adjacent non-tumor specimens. mLST8 overexpression positively correlated with tumor size, differentiation, and vessel invasion. Cases with elevated mLST8 level had more unfavorable overall survival (OS) and disease-free survival (DFS) than those with downregulated mLST8 level. Multivariate analysis demonstrated that mLST8 upregulation was an independent predictive marker for OS and DFS. Calibration curves from nomogram models indicated an excellent coherence between nomogram prediction and actual situation. Decision curve analysis proved that mLST8-based nomograms presented much higher predictive accuracy when compared with conventional clinical staging systems. Mechanistically, mLST8 enhanced cell proliferation and invasion through the AKT (protein kinase B) pathway. CONCLUSIONS: Our study demonstrates that mLST8 exerts an oncogenic role in HCC and may become a promising prognostic biomarker and therapeutic target for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Homólogo LST8 da Proteína Associada a mTOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nomogramas , Prognóstico , Regulação para Cima , Adulto Jovem
4.
Yi Chuan ; 37(2): 148-156, 2015 Feb.
Artigo em Zh | MEDLINE | ID: mdl-25665641

RESUMO

Segregation distortion (SD) is defined as abnormal segregation ratio of hybrid offsprings at some genetic loci deviating from the Mendelian ratio. SD results from the incompatibility among genes from different parents, which could be due to loss-of-function or gain-of-function gene interactions. The mechanism for loss-of-function SD is relatively simple: defective gene combination leads to loss of the original function and eventual cell death. The gain-of-function hybrid SD system is a multi-gene genetic system, comprising two basic components: the killer and the protector. Additional modifiers, such as enhancers and repressors, are also involved. There is a general genetic model for gain-of-function hybrid SD: haplotypes with transmission advantage possess high-activity killer⁺ and protector⁺; those with transmission disadvantage possess low-activity killer- and protector-; neutral haplotypes (wide compatibility types) possess killer- and protector⁺. Depending upon close linkage between the killer and the protector and the accumulation of modifiers, the SD system survived through natural selection. Although the genetic mechanisms are highly similar, different gain-of-function hybrid SD systems have distinctive molecular mechanisms. In this review, we summarize the genetic and molecular mechanisms of hybrid SD, and the relationship between hybrid SD and hybrid sterility.


Assuntos
Segregação de Cromossomos , Hibridização Genética , Animais , Drosophila/genética , Humanos , Camundongos , Oryza/genética
5.
Hepatol Int ; 18(2): 636-650, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37982952

RESUMO

BACKGROUND: Aberrant iron metabolism is commonly observed in multiple tumor types, including hepatocellular carcinoma (HCC). However, as the key regulator of iron metabolism involved in iron absorption, the role of transferrin receptor (TFRC) in HCC remains elusive. METHODS: The mRNA and protein expression of TFRC were evaluated in paired HCC and adjacent non-tumor specimens. The correlation between TFRC level and clinicopathological features or prognostic significance was also analyzed. The role of TFRC on biological functions was finally studied in vitro and in vivo. RESULTS: The TFRC level was remarkably upregulated in HCC tissues compared to paired peritumor tissues. Overexpressed TFRC positively correlated with serum alpha-fetoprotein, carcinoembryonic antigen, and poor tumor differentiation. Multivariate analysis demonstrated that upregulated TFRC was an independent predictive marker for poorer overall survival and disease-free survival in HCC patients. Loss of TFRC markedly impaired cell proliferation and migration in vitro and notably suppressed HCC growth and metastasis in vivo, while overexpression of TFRC performed an opposite effect. Mechanistically, the mTOR signaling pathway was downregulated with TFRC knockdown, and the mTOR agonist MHY1485 completely reversed the biological inhibition in HCC cells caused by TFRC knockdown. Furthermore, exogenous ferric citrate (FAC) or iron chelator reversed the changed biological functions and signaling pathway expression of HCC cells caused by TFRC knockdown or overexpression, respectively. CONCLUSIONS: Our study indicates that TFRC exerts an oncogenic role in HCC and may become a promising therapeutic target to restrain HCC progression.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Ferro/metabolismo , Neoplasias Hepáticas/patologia , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
6.
Cancer Res ; 84(11): 1817-1833, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38484085

RESUMO

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy. SIGNIFICANCE: CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients.


Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Macrófagos , Transdução de Sinais , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Quimiocina CCL2/imunologia , Imunoterapia/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia
7.
Colloids Surf B Biointerfaces ; 245: 114279, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39368423

RESUMO

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), has limited clinical application due to severe side effects and drug resistance. To overcome these challenges, we developed a bismuth-based nanomaterial (BOS) for thermal injury-assisted continuous targeted therapy in HCC. Initially, the mesoporous nanomaterial was loaded with SOR, forming the BOS@SOR nano-carrier system for drug delivery and controlled release. Notably, compared to targeted or photothermal therapy alone, the combination therapy using this nano-carrier system significantly impaired cell proliferation and increased apoptosis. In vivo efficacy evaluations demonstrated that BOS@SOR exhibited excellent biocompatibility, confirmed through hemolysis and biochemical analyses. Additionally, BOS@SOR enhanced contrast in computed tomography, aiding in the precise identification of HCC size and location. The photothermal therapeutic properties of bismuth further contributed to the synergistic anti-tumor activity of BOS@SOR, significantly reducing tumor growth in an orthotopic xenograft HCC model. Taken together, encapsulating SOR within a bismuth-based mesoporous nanomaterial creates a multifunctional and environmentally stable nanocomposite (BOS@SOR), enhancing the therapeutic effect of SOR and presenting an effective strategy for HCC treatment.

8.
Int J Biol Sci ; 20(7): 2763-2778, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725845

RESUMO

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Carcinoma Hepatocelular , Neoplasias Hepáticas , Linfócitos T Reguladores , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Humanos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase/genética , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Multiômica
9.
Cancer Res ; 83(4): 521-537, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36723974

RESUMO

Lipid metabolism reprogramming is a recognized hallmark of cancer cells. Identification of the underlying regulators of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) could uncover potential therapeutic targets to improve treatment. Here, we demonstrated that pre-mRNA processing factor 19 (PRP19) mediates reprogramming of lipid metabolism in ESCC. Expression of PRP19 was significantly upregulated in multiple ESCC cohorts and was correlated with poor clinical prognosis. PRP19 promoted ESCC proliferation in vitro and in vivo. Upregulation of PRP19 enhanced fatty acid synthesis through sterol regulatory element-binding protein 1 (SREBF1), a major transcription factor of lipid synthase. Moreover, PRP19 enhanced the stability of SREBF1 mRNA in an N6-methyladenosine-dependent manner. Overall, this study shows that PRP19-mediated fatty acid metabolism is crucial for ESCC progression. Targeting PRP19 is a potential therapeutic approach to reverse metabolic reprogramming in patients with ESCC. SIGNIFICANCE: Upregulation of pre-mRNA processing factor 19 (PRP19) contributes to esophageal squamous cell carcinoma progression by reprogramming SREBF1-dependent fatty acid metabolism, identifying PRP19 as a potential prognostic biomarker and therapeutic target.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Ácidos Graxos , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Prognóstico , Precursores de RNA/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
10.
Adv Healthc Mater ; 12(27): e2301133, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37311013

RESUMO

Ferroptosis is identified as a novel type of cell death with distinct properties involved in physical conditions and various diseases, including cancers. It is considered that ferroptosis provides a promising therapeutic strategy for optimizing oncotherapy. Although erastin is an effective ferroptosis trigger, the potential of its clinical application is largely restricted by its poor water solubility and concomitant limitations. To address this issue, an innovative nanoplatform (PE@PTGA) that integrated protoporphyrin IX (PpIX) and erastin coated with amphiphilic polymers (PTGA) to evoke ferroptosis and apoptosis is constructed and exemplified using an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model as a paradigm. The self-assembled nanoparticles can enter HCC cells and release PpIX and erastin. With light stimulation, PpIX exerts hyperthermia and reactive oxygen species to inhibit the proliferation of HCC cells. Besides, the accumulated reactive oxygen species (ROS) can further promote erastin-induced ferroptosis in HCC cells. In vitro and in vivo studies reveal that PE@PTGA synergistically inhibits tumor development by stimulating both ferroptosis- and apoptosis-related pathways. Moreover, PE@PTGA has low toxicity and satisfactory biocompatibility, suggesting its promising clinical benefit in cancer treatments.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Pró-Fármacos , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral
11.
Nanomaterials (Basel) ; 12(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36144982

RESUMO

Hepatocellular carcinoma (HCC) accounts for the predominant form of liver malignancy and presents a leading cause of cancer-related death globally. Sorafenib (SOR), a first-line targeted drug for advanced HCC treatment, has a battery of untoward side effects. Photothermal therapy (PTT) has been utilized as an effective adjuvant in synergy with other approaches. However, little is known about the tumoricidal efficacy of combining SOR with PTT for HCC. Herein, a novel versatile nanoparticle, Cu2-xSe@SOR@PEG (CSP), that is based on a photothermal Cu2-xSe core and SOR for simultaneously reinforcing PTT and reducing the adverse effects of SOR was constructed. The synthesized CSP exhibited a remarkably enhanced therapeutic effect upon 808 nm laser irradiation via dampening HCC cell propagation and metastasis and propelling cell apoptosis. The intravenous administration of CSP substantially suppressed tumor growth in a xenograft tumor mouse model. It was noted that the CSP manifested low toxicity and excellent biocompatibility. Together, this work indicates a promising and versatile tool that is based on synergistic PTT and molecular-targeted therapy for HCC management.

12.
ACS Appl Mater Interfaces ; 14(33): 37356-37368, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-35951459

RESUMO

Although sorafenib, a multi-kinase inhibitor, has provided noteworthy benefits in patients with hepatocellular carcinoma (HCC), the inevitable side effects, narrow therapeutic window, and low bioavailability seriously affect its clinical application. To be clinically distinctive, innovative drugs must meet the needs of reaching tumor tissues and cause limited side effects to normal organs and tissues. Recently, photodynamic therapy, utilizing a combination of a photosensitizer and light irradiation, was selectively accumulated at the tumor site and taken up effectively via inducing apoptosis or necrosis of cancer cells. In this study, a nano-chemo-phototherapy drug was fabricated to compose an iridium-based photosensitizer combined with sorafenib (IPS) via a self-assembly process. Compared to the free iridium photosensitizer or sorafenib, the IPS exhibited significantly improved therapeutic efficacy against tumor cells because of the increased cellular uptake and the subsequent simultaneous release of sorafenib and generation of reactive oxygen species production upon 532 nm laser irradiation. To evaluate the effect of synergistic treatment, cytotoxicity detection, live/dead staining, cell proliferative and apoptotic assay, and Western blot were performed. The IPS exhibited sufficient biocompatibility by hemolysis and serum biochemical tests. Also, the results suggested that IPS significantly inhibited HCC cell proliferation and promoted cell apoptosis. More importantly, marked anti-tumor growth effects via inhibiting cell proliferation and promoting tumor cell death were observed in an orthotopic xenograft HCC model. Therefore, our newly proposed nanotheranostic agent for combined chemotherapeutic and photodynamic therapy notably improves the therapeutic effect of sorafenib and has the potential to be a new alternative option for HCC treatment.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanocompostos , Fotoquimioterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Irídio/farmacologia , Neoplasias Hepáticas/patologia , Nanocompostos/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Sorafenibe/uso terapêutico
13.
Front Pharmacol ; 13: 952482, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071851

RESUMO

Sorafenib resistance is often developed and impedes the benefits of clinical therapy in hepatocellular carcinoma (HCC) patients. However, the relationship between sorafenib resistance and tumor immune environment and adjuvant drugs for sorafenib-resistant HCC are not systemically identified. This study first analyzed the expression profiles of sorafenib-resistant HCC cells to explore immune cell infiltration levels and differentially expressed immune-related genes (DEIRGs). The prognostic value of DEIRGs was analyzed using Cox regression and Kaplan-Meier analysis based on The Cancer Genome Atlas. The primary immune cells infiltrated in sorafenib-resistant HCC mice were explored using flow cytometry (FCM). Finally, small-molecule drugs for sorafenib-resistant HCC treatment were screened and validated by experiments. The CIBERSORT algorithm and mice model showed that macrophages and neutrophils are highly infiltrated, while CD8+ T cells are downregulated in sorafenib-resistant HCC. Totally, 34 DEIRGs were obtained from sorafenib-resistant and control groups, which were highly enriched in immune-associated biological processes and pathways. NR6A1, CXCL5, C3, and TGFB1 were further identified as prognostic markers for HCC patients. Finally, nalidixic acid was identified as a promising antagonist for sorafenib-resistant HCC treatment. Collectively, our study reveals the tumor immune microenvironment changes and explores a promising adjuvant drug to overcome sorafenib resistance in HCC.

14.
Aging (Albany NY) ; 12(3): 2373-2392, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32012120

RESUMO

Upregulated ubiquitin-conjugating enzyme E2M (UBE2M) is associated with poor prognosis in malignancies; However, the phenotype and mechanism of action of UBE2M in hepatocellular carcinoma (HCC) remain elusive. Here, we report that UBE2M is overexpressed and correlated with poor prognosis in HCC patients. The UBE2M level is an independent prognostic factor for HCC patients. UBE2M knockdown inhibits HCC cell proliferation, migration, and invasion, whereas its overexpression has an opposite effect. Mechanistically, upregulated UBE2M exerts oncogenic effects by translocation of accumulated ß-catenin from the cytoplasm to the nucleus, thus activating downstream ß-catenin/cyclin D1 signaling. In summary, our study demonstrates a notable role of UBE2M in promoting the growth of HCC, providing a novel strategy for HCC prevention and treatment.


Assuntos
Carcinoma Hepatocelular/patologia , Ciclina D1/metabolismo , Neoplasias Hepáticas/patologia , Enzimas de Conjugação de Ubiquitina/metabolismo , beta Catenina/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/análise , Proliferação de Células/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/fisiologia
15.
Cancer Med ; 9(22): 8318-8332, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955798

RESUMO

Identifying novel prognostic biomarkers for hepatocellular carcinoma (HCC) and then, develop an effective individualized treatment strategy remain extremely warranted. The prognostic role of sulfiredoxin-1(SRXN1), an antioxidant enzyme, remains unknown in HCC. This study aimed to explore the prognostic implications of SRXN1 in HCC patients after partial hepatectomy. The expression of SRXN1 in HCC and normal tissue were analyzed using the patients from the public databases and Zhongshan Hospital. The Cox regression, Kaplan-Meier survival analysis, and time-dependent receiver operating characteristic curves were performed to identify the predictive role of SRXN1 expression on HCC patients. A prognostic nomogram based on SRXN1 expression was constructed and validated to further confirm the predictive power of SRXN1 as a prognostic biomarker. Finally, functional enrichment analysis and protein-protein interaction network analysis of SRXN1 and its associated genes were conducted. The results showed that SRXN1 was upregulated in HCC samples compared with the normal liver tissues. Patients with SRXN1 upregulation had shorter survival time. SRXN1 overexpression was significantly correlated with advanced clinicopathological parameters. The prognostic nomogram based on SRXN1 expression was proved to be more accurate than routine staging systems for the prediction of overall survival. Protein-protein interaction network analysis demonstrated the first neighbor genes of SRXN1 mainly participated in response to oxidative stress. In brief, SRXN1 could be a prognostic biomarker for the management of HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Bases de Dados Genéticas , Técnicas de Apoio para a Decisão , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Hepatectomia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Nomogramas , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Valor Preditivo dos Testes , Mapas de Interação de Proteínas , Transdução de Sinais , Fatores de Tempo , Resultado do Tratamento
16.
Oncogene ; 39(35): 5768-5781, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32719439

RESUMO

Cumulative evidence suggests that microRNAs (miRNAs) promote gene expression in cancers. However, the pathophysiologic relevance of miRNA-mediated RNA activation in hepatocellular carcinoma (HCC) remains to be established. Our previous miRNA expression profiling in seven-paired HCC specimens revealed miR-93-5p as an HCC-related miRNA. In this study, miR-93-5p expression was assessed in HCC tissues and cell lines by quantitative real-time PCR and fluorescence in situ hybridization. The correlation of miR-93-5p expression with survival and clinicopathological features of HCC was determined by statistical analysis. The function and potential mechanism of miR-93-5p in HCC were further investigated by a series of gain- or loss-of-function experiments in vitro and in vivo. We identified that miR-93-5p, overexpressed in HCC specimens and cell lines, leads to poor outcomes in HCC cases and promotes proliferation, migration, and invasion in HCC cell lines. Mechanistically, rather than decreasing target mRNA levels as expected, miR-93-5p binds to the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to directly upregulate its expression and downstream p38 and c-Jun N-terminal kinase (JNK) pathway, thereby leading to cell cycle progression in HCC. Notably, we also demonstrated that c-Jun, a downstream effector of the JNK pathway, enhances miR-93-5p transcription by targeting its promoter region. Besides, downregulation of miR-93-5p significantly retarded tumor growth, while overexpression of miR-93-5p accelerated tumor growth in the HCC xenograft mouse model. Altogether, we revealed a miR-93-5p/MAP3K2/c-Jun positive feedback loop to promote HCC progression in vivo and in vitro, representing an RNA-activating role of miR-93-5p in HCC development.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase Quinase 2/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Regiões 3' não Traduzidas , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinase 2/biossíntese , MAP Quinase Quinase Quinase 2/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Fosforilação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-jun/genética , Transfecção , Regulação para Cima
17.
Mol Med Rep ; 11(3): 1891-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25385552

RESUMO

The aim of the present study was to investigate the effects of small interfering RNA­mediated inhibition of Class III phosphoinositide 3­kinase (PI3K) signal transduction on the proliferation, apoptosis and autophagy of SGC7901 gastric cancer cells. The present study also aimed to examine the contribution of autophagic inhibition to the antitumor effects of 5­fluorouracil (5­FU). A PI3K(III)­RNA interference (i)­green fluorescent protein (GFP) recombinant replication adenovirus (AD) and the negative control (NC)­RNAi­GFP control AD were constructed and infected into SGC7901 cells. A methyl thiazolyl tetrazolium assay was used to determine the growth rate of the SGC7901 cells. Immunofluorescent staining was used to detect microtubule­associated protein 1 light chain 3 expression. The mitochondrial membrane potential was measured using the JC­1 fluorescent probe. Autophagic expression was monitored with MDC staining and transmission electron microscopy. The results revealed that following combination treatment of the SGC7901 gastric cancer cells with 5­FU + PI3K(III)­RNAi­AD, the optical density absorbance values at 24, 48 and 72 h were 0.17 ± 1.64, 0.13 ± 4.64 and 0.11 ± 3.56%, respectively, with cell viability inhibition ratios of 45.89 ± 6.67, 72.57 ± 9.48 and 87.51 ± 4.65%, respectively. As compared with the other treatment groups, the inhibition rate in the combined treatment group was significantly higher (P<0.05). The percentages of the cells with green fluorescence in the combined treatment group were 74.4 ± 3.86 (24 h), 82.3 ± 1.84 (48 h) and 92.5 ± 1.1% (72 h), which were larger than those of the other groups. The percentage of cells with green fluorescence became larger, which indicated that the mitochondrion membrane potential had been reduced to a greater extent. MDC staining revealed that the number of autophagic vacuoles in the cells (measured at 24, 48 and 72 h) decreased gradually with time, with more autophagic vacuoles observed in the cells in the control group at 24 h than those in the other treatment groups. Fewest autophagic vacuoles were identified in the combined treatment group. Using a fluorescence microscope, the immune fluorescence expression of microtubule­associated proteins 1A/1B light chain 3A, which is the specific protein of autophagy, in the combined treatment group was observed to be significantly downregulated, as compared with the other groups. As determined by transmission electron microscopic observation of the SGC7901 gastric cancer cells, the degree of autophagy in the combined treatment group was significantly reduced, as compared with that of the other treatment groups. In conclusion, following combined treatment with 5­FU and an inhibitor of class III PI3K signal transduction, the proliferation of SGC7901 cells was significantly suppressed, the mitochondrion membrane potentials were significantly reduced and the expression levels of autophagic markers were significantly downregulated.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fluoruracila/farmacologia , Fosfatidilinositol 3-Quinases/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenoviridae/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Fluoruracila/administração & dosagem , Expressão Gênica , Vetores Genéticos/genética , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Transdução Genética , Transfecção
18.
Zhonghua Wei Chang Wai Ke Za Zhi ; 16(5): 484-8, 2013 May.
Artigo em Zh | MEDLINE | ID: mdl-23696410

RESUMO

OBJECTIVE: To investigate the effect of recombinant adenovirus (phosphatidylinositol-3-kinases(PI3K)(I()-RNAi-AD which blocks the class I( PI3K signaling pathway on gastric carcinoma cells xenografts in nude mice. METHODS: Subcutaneous tumor models of nude mice were established with SGC7901 cells and randomly divided into PI3K(I()-RNAi-AD group, NC-RNAi-GFP-AD group and control group. The tumor size and the inhibitory rate of tumor growth on days 3, 6, and 9 after cell transplantation were measured. The expression of TNF-α, COX2, P53, PCNA, E-cadherin and nm23/DNPK in tumor tissues were detected by immunohistochemistry. RESULTS: Tumor growth was significantly inhibited in the PI3K(I()-RNAi-AD group(14.2%, 21.0%, and 28.1%) on days 3, 6, 9 compared with NC-RNAi-GFP-AD group(1.3%, 1.9%, and 2.0%, all P<0.05). The expressions of TNF-α, P53, E-cadherin and nm23/DNPK were up-regulated, and the expressions of COX2 and PCNA were down-regulated in the PI3K(I()-RNAi-AD group by immunohistochemical staining(all P<0.05). CONCLUSIONS: PI3K(I()-RNAi-AD can inhibit the growth of SGC7901 cell transplantation tumor in vivo in nude mice by inhibiting cell growth, reducing the capacity of tumor invasion and inhibiting tumor angiogenesis.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Gástricas , Adenoviridae , Animais , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases , Fosfatidilinositóis
19.
Zhonghua Wei Chang Wai Ke Za Zhi ; 14(5): 364-7, 2011 May.
Artigo em Zh | MEDLINE | ID: mdl-21614693

RESUMO

OBJECTIVE: To investigate the effect of phosphatidylinositol 3-kinase inhibitor LY294002 combined with NF-κB P65 nuclear translocation inhibitor SN50 on the tumor cell growth and apoptosis using a nude mouse model of gastric cancer. METHODS: Human gastric cancer cell strain SGC7901 was transplanted subcutaneously to nude mice to establish tumor models. Model mice were randomly divided into the control group, the LY294002 treatment group, the SN50 treatment group, and the LY294002+SN50 treatment group, with 5 in each group. After being treated for 10 days, the inhibition rate of tumor growth was ascertained by measuring the size of tumor. Immunohistochemical method was used to detect the expression levels of Bcl-2, P53 and Bax proteins and transmission electron microscopy to investigate the apoptosis of tumor cells. RESULTS: On the 10th day after treatment, the inhibition rate of gastric cancer cellular growth in the LY294002+SN50 group was (49.2±2.5)%, which was significantly higher than that in the LY294002 group(29.4±1.5)% and SN50 group (19.7±1.6)%(P<0.05). In comparison with the other two groups, LY294002+SN50 group exhibited more severe apoptosis, with expression of Bcl-2 decreased and that of P53 and Bax increased more significantly(P<0.05). CONCLUSION: LY294002 combined with SN50 inhibits the growth of SGC7901 transplanted tumor and aggravates the apoptosis of gastric cancer cells in nude mice model.


Assuntos
Cromonas/farmacologia , Morfolinas/farmacologia , Peptídeos/farmacologia , Neoplasias Gástricas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
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