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1.
Biomaterials ; 312: 122740, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39096839

RESUMO

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.


Assuntos
Asparaginase , Inibidores de Checkpoint Imunológico , Imunoterapia , Animais , Asparaginase/uso terapêutico , Asparaginase/farmacologia , Asparaginase/química , Imunoterapia/métodos , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Humanos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Elastina/química , Elastina/metabolismo , Metástase Neoplásica , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Distribuição Tecidual
2.
Gene ; 932: 148908, 2025 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-39218414

RESUMO

BACKGROUND: Although progress has been made in accurate diagnosis and targeted treatments, breast cancer (BC) patients with metastasis still present a grim prognosis. With the continuous emergence and development of new personalized and precision medicine targeting specific tumor biomarkers, there is an urgent need to find new metastatic and prognostic biomarkers for BC patients. METHODS: We were dedicated to identifying genes linked to metastasis and prognosis in breast cancer through a combination of in silico analysis and experimental validation. RESULTS: A total of 25 overlap differentially expressed genes were identified. Ten hub genes (namely MRPL13, CTR9, TCEB1, RPLP0, TIMM8B, METTL1, GOLT1B, PLK2, PARL and MANBA) were identified and confirmed. MRPL13, TCEB1 and GOLT1B were shown to be associated with the worse overall survival (OS) and were optionally chosen for further verification by western blot. Only MRPL13 was found associated with cell invasion, and the expression of MRPL13 in metastatic BC was significantly higher than in primary BC. CONCLUSION: We proposed MRPL13 could be a potential novel biomarker for the metastasis and prognosis of breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Simulação por Computador , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Perfilação da Expressão Gênica/métodos , Linhagem Celular Tumoral , Pessoa de Meia-Idade
3.
Technol Cancer Res Treat ; 23: 15330338241281310, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39267432

RESUMO

Purpose: To investigate the inhibitory effect of antimicrobial peptide merecidin on triple-negative breast cancer (TNBC) and the mechanism of inhibiting epithelial-mesenchymal transformation (EMT) by regulating miR-30d-5p/vimentin. Methods: TNBC cell lines (MDA-MB-231, MDA-MB-468) were treated with merecidin to assess proliferation, migration, invasion ability, and EMT. Confocal laser localization was used to examine the role of merecidin and TNBC cells. The relationship between merecidin and miR-30d-5p was determined through RT-qPCR and dual-luciferase reporter gene, and the relationship between merecidin and vimentin was verified through pulling down the experiment. The effects of miR-30d-5p on the migration and invasion ability of TNBC cells were confirmed through scratch and transwell experiments. Vimentin levels, tumor volume, shape, size, and weight were observed in the MDA-MB-231 subcutaneous tumor model in nude mice. Results: merecidin inhibited the proliferation, migration, invasion, and EMT of TNBC cells. merecidin was primarily located in the cytoplasm of TNBC cells, and the expression of miR-30d-5p was low in TNBC cells. merecidin significantly up-regulated the expression of miR-30d-5p. miR-30d-5p negatively regulated vimentin. merecidin could bind to vimentin in vitro. miR-30d-5p inhibited the migration and invasion ability of TNBC cells, while vimentin promoted their migration and invasion ability. Down-regulation of miR-30d-5p or overexpression of vimentin partially counteracted the inhibitory effects of merecidin on TNBC cell migration, invasion ability, and EMT. In nude mouse tumor models, merecidin significantly suppressed tumor growth. Conclusion: Merecidin effectively blocks the EMT process and inhibits the migration and invasion of TNBC cells by regulating miR-30d-5p/vimentin.


Assuntos
Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias de Mama Triplo Negativas , Vimentina , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , MicroRNAs/genética , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Vimentina/metabolismo , Camundongos , Feminino , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Modelos Animais de Doenças , Metástase Neoplásica , Peptídeos Catiônicos Antimicrobianos/farmacologia
4.
Neoplasma ; 71(4): 347-358, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39267538

RESUMO

Breast cancer is the most common malignant tumor in women. Recurrence, metastasis, and chemotherapy resistance are the main causes of death in breast cancer patients. The inhibition of breast cancer metastasis is of great significance for prolonging its survival. Ribosome biogenesis regulatory protein homolog (RRS1) is overexpressed in breast cancer tissues and is involved in regulating the carcinogenic process of breast cancer cells. However, the exact signaling pathway and molecular mechanism of RRS1 promoting breast cancer metastasis are not fully understood. Hence, the primary objective of our study is to investigate the correlation between RRS1 and breast cancer metastasis. Bioinformatic analysis was used to identify the expression levels and prognostic significance of RRS1 in breast cancer. Lenti-sh RRS1 lentivirus was constructed and employed to downregulate the RRS1 expression in MDA-MB-231 and BT549 cells, which had a high-level expression of RRS1. Subsequently, we assessed the impact of RRS1 downregulation on the proliferation, migration, and invasion of breast cancer cells using CCK-8, apoptosis, and cell cycle by flow cytometry, wound healing test, Transwell migration, and invasion experiments. Moreover, we utilized an in vivo imaging system to examine the metastatic potential of breast cancer cells after RRS1 knockdown. Picrate staining and hematoxylin-eosin staining were employed to evaluate the presence of metastatic lesions. To gain a deeper understanding of the molecular mechanism, we conducted co-immunoprecipitation and western blot. The significant overexpression of RRS1 in breast cancer indicates a worse prognosis, as determined through TCGA databases (p<0.01). Additionally, RRS1 exhibits upregulation in breast cancer (p<0.001), which is tightly linked to the occurrence of lymph node metastasis (p<0.001). Clinical breast cancer tissues and breast cancer cell lines also demonstrated a noteworthy upregulation of RRS1 (p<0.05). Loss-of-function experiment illustrated that the inhibiting of RRS1 expression reduced the rapid proliferation capacity of MDA-MB-231 and BT549 cells and hindered their migration and invasion capabilities (p<0.05). Importantly, the suppression of RRS1 significantly diminished lung metastasis in Balb/c nude mice that were injected with MDA-MB-231 cells (p<0.01). Mechanistically, RRS1 may interact with the AEG-1 to modulate the phosphorylation of AKT at T308 and S473, consequently impeding the activity of c-Myc (p<0.05). To conclude, RRS1 functions as a potential oncogene in breast cancer by leveraging the AEG-1/AKT/c-Myc signaling.


Assuntos
Neoplasias da Mama , Movimento Celular , Proliferação de Células , Proteínas de Membrana , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-myc , Proteínas de Ligação a RNA , Transdução de Sinais , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Animais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Apoptose , Prognóstico , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Camundongos Nus , Invasividade Neoplásica , Camundongos Endogâmicos BALB C
5.
Sci Rep ; 14(1): 21451, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271782

RESUMO

Based on the joint analysis of multi-omic data and the biological experiments, we demonstrate that FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via regulating MFAP4/FAK signal axis in this study. The levels of FOXF1 and MFAP4 are significantly down-regulated in LUAD, and the increased levels of two genes can improve the clinical prognosis of LUAD patients. Fluorescein reporter gene determination, chromatin immunoprecipitation and gene co-expression analysis indicate that MFAP4 level is positively regulated by transcription factor FOXF1. The function enrichment analysis shows that the levels of FOXF1 and MFAP4 are closely associated with an enrichment of tumor metastasis signatures. FOXF1 can inhibit the migration and invasion of LAUD cells by transcriptionally activating MFAP4 expression. And the overexpression of FOXF1/MFAP4 can reduce focal adhesion kinase (FAK) phosphorylation, while their knockdown result in the opposite effects. The increased levels of FOXF1/MFAP4 enhance the antitumor immunity by increasing the infiltration of dendritic cells and CD4+ T cells, and the interactions between LUAD cells and immune cells, and activating multiple anti-tumor immunity-related pathways. In conclusion, our study reveals the potential function of FOXF1/MFAP4/FAK signal axis in inhibiting metastasis of LUAD cells and modulating anti-tumor immunity of LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Fatores de Transcrição Forkhead , Neoplasias Pulmonares , Invasividade Neoplásica , Transdução de Sinais , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Movimento Celular , Camundongos , Animais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo
6.
BMC Immunol ; 25(1): 60, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39271997

RESUMO

BACKGROUND: Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). ß-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received ß-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis. RESULTS: Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0-6.6] and 9.8 months [95% CI: 7.2-12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response. CONCLUSION: ß-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , beta-Glucanas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Idoso , Pessoa de Meia-Idade , beta-Glucanas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Metástase Neoplásica , Resultado do Tratamento
7.
Mol Cancer ; 23(1): 198, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39272149

RESUMO

Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-κB pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.


Assuntos
Exossomos , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular , MicroRNAs , Proteínas do Tecido Nervoso , Neutrófilos , Neoplasias Gástricas , Microambiente Tumoral , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Exossomos/metabolismo , Exossomos/genética , Humanos , Neutrófilos/metabolismo , Neutrófilos/patologia , MicroRNAs/genética , Animais , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Microambiente Tumoral/genética , Metástase Neoplásica , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Masculino
8.
J Nanobiotechnology ; 22(1): 562, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39272180

RESUMO

BACKGROUND: Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle. RESULTS: Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8+ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier. CONCLUSIONS: Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses.


Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Ferritinas , Camundongos Endogâmicos C57BL , Nanopartículas , Animais , Ferritinas/química , Antígenos de Neoplasias/imunologia , Nanopartículas/química , Vacinas Anticâncer/imunologia , Camundongos , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunoterapia/métodos , Metástase Neoplásica , Humanos , Linfonodos , Proteínas Recombinantes
9.
Cell Death Dis ; 15(9): 675, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39277583

RESUMO

Rap2b, a proto-oncogene upregulated in colorectal cancer (CRC), undergoes protein S-palmitoylation at specific C-terminus sites (C176/C177). These palmitoylation sites are crucial for Rap2b localization on the plasma membrane (PM), as mutation of C176 or C177 results in cytosolic relocation of Rap2b. Our study demonstrates that Rap2b influences cell migration and invasion in CRC cells, independent of proliferation, and this activity relies on its palmitoylation. We identify ABHD17a as the depalmitoylating enzyme for Rap2b, altering PM localization and inhibiting cell migration and invasion. EGFR/PI3K signaling regulates Rap2b palmitoylation, with PI3K phosphorylating ABHD17a to modulate its activity. These findings highlight the potential of targeting Rap2b palmitoylation as an intervention strategy. Blocking the C176/C177 sites using an interacting peptide attenuates Rap2b palmitoylation, disrupting PM localization, and suppressing CRC metastasis. This study offers insights into therapeutic approaches targeting Rap2b palmitoylation for the treatment of metastatic CRC, presenting opportunities to improve patient outcomes.


Assuntos
Membrana Celular , Movimento Celular , Neoplasias Colorretais , Lipoilação , Proto-Oncogene Mas , Proteínas rap de Ligação ao GTP , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap de Ligação ao GTP/genética , Membrana Celular/metabolismo , Animais , Linhagem Celular Tumoral , Metástase Neoplásica , Transdução de Sinais , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Receptores ErbB/metabolismo , Proliferação de Células
10.
Mol Cancer ; 23(1): 200, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39277750

RESUMO

Metastasis has been one of the primary reasons for the high mortality rates associated with tumours in recent years, rendering the treatment of current malignancies challenging and representing a significant cause of recurrence in patients who have undergone surgical tumour resection. Halting tumour metastasis has become an essential goal for achieving favourable prognoses following cancer treatment. In recent years, increasing clarity in understanding the mechanisms underlying metastasis has been achieved. The concept of premetastatic niches has gained widespread acceptance, which posits that tumour cells establish a unique microenvironment at distant sites prior to their migration, facilitating their settlement and growth at those locations. Neutrophils serve as crucial constituents of the premetastatic niche, actively shaping its microenvironmental characteristics, which include immunosuppression, inflammation, angiogenesis and extracellular matrix remodelling. These characteristics are intimately associated with the successful engraftment and subsequent progression of tumour cells. As our understanding of the role and significance of neutrophils in the premetastatic niche deepens, leveraging the presence of neutrophils within the premetastatic niche has gradually attracted the interest of researchers as a potential therapeutic target. The focal point of this review revolves around elucidating the involvement of neutrophils in the formation and shaping of the premetastatic niche (PMN), alongside the introduction of emerging therapeutic approaches aimed at impeding cancer metastasis.


Assuntos
Metástase Neoplásica , Neoplasias , Neutrófilos , Microambiente Tumoral , Humanos , Neutrófilos/metabolismo , Neutrófilos/patologia , Neoplasias/patologia , Neoplasias/terapia , Neoplasias/metabolismo , Animais
11.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39273106

RESUMO

We reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcomes. Here, we analysed a breast cancer xenograft with or without enforced expression of BMP4 to gain insight into the mechanisms by which BMP4 suppresses metastasis. Transcriptomic analysis of cancer cells recovered from primary tumours and phosphoproteomic analyses of cancer cells exposed to recombinant BMP4 revealed that BMP4 inhibits cholesterol biosynthesis, with many genes in this biosynthetic pathway being downregulated by BMP4. The treatment of mice bearing low-BMP4 xenografts with a cholesterol-lowering statin partially mimicked the anti-metastatic activity of BMP4. Analysis of a cohort of primary breast cancers revealed a reduced relapse rate for patients on statin therapy if their tumours exhibited low BMP4 levels. These findings indicate that BMP4 may represent a predictive biomarker for the benefit of additional statin therapy in breast cancer patients.


Assuntos
Proteína Morfogenética Óssea 4 , Neoplasias da Mama , Colesterol , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Humanos , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 4/genética , Feminino , Animais , Colesterol/biossíntese , Colesterol/metabolismo , Camundongos , Linhagem Celular Tumoral , Metástase Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
12.
Int J Mol Sci ; 25(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39273294

RESUMO

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan-Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003-0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011-0.260; p < 0.0001). The Kaplan-Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071-0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05-0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2-3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5-9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.


Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Proteômica , Transcriptoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Melanoma/mortalidade , Feminino , Masculino , Estudos Retrospectivos , Proteômica/métodos , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Biomarcadores Tumorais/genética , Adulto , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/metabolismo , Metástase Neoplásica
13.
Int J Mol Sci ; 25(17)2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39273642

RESUMO

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.


Assuntos
Imunoconjugados , Humanos , Imunoconjugados/uso terapêutico , Metástase Neoplásica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Camptotecina/análogos & derivados
14.
Int J Mol Sci ; 25(17)2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39273689

RESUMO

Malignant breast cancers pose a notable challenge when it comes to treatment options. Recently, research has implicated extracellular vesicles (EVs) secreted by cancer cells in the formation of a pre-metastatic niche. Small clumps of CD44-positive breast cancer cells are efficiently transferred through CD44-CD44 protein homophilic interaction. This study aims to examine the function of CD44-positive EVs in pre-metastatic niche formation in vitro and to suggest a more efficacious EV formulation. We used mouse mammary carcinoma cells, BJMC3879 Luc2 (Luc2 cells) as the source of CD44-positive EVs and mouse endothelial cells (UV2 cells) as the recipient cells in the niche. Luc2 cells exhibited an enhanced secretion of EVs expressing CD44 and endothelial growth factors (VEGF-A, -C) under 20% O2 (representative of the early stage of tumorigenesis) compared to its expression under 1% O2 (in solid tumor), indicating that pre-metastatic niche formation occurs in the early stage. Furthermore, UV2 endothelial cells expressing CD44 demonstrated a high level of engulfment of EVs that had been supplemented with hyaluronan, and the proliferation of UV2 cells occurred following the engulfment of EVs. These results suggest that anti-VEGF-A and -C encapsulated, CD44-expressing, and hyaluronan-coated EVs are more effective for tumor metastasis.


Assuntos
Vesículas Extracelulares , Receptores de Hialuronatos , Animais , Receptores de Hialuronatos/metabolismo , Vesículas Extracelulares/metabolismo , Camundongos , Feminino , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Metástase Neoplásica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proliferação de Células , Microambiente Tumoral , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Ácido Hialurônico/metabolismo
15.
Cancer Lett ; 603: 217195, 2024 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-39222678

RESUMO

TGF-ß-SMAD signaling pathway plays an important role in the progression of various cancers. However, posttranscriptional regulation such as N6-methyladenosine (m6A) of TGF-ß-SMAD signaling axis remains incompletely understood. Here, we reveal that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is low expression as well as associated with poor prognosis in clear cell renal cell carcinoma (ccRCC) patients and inhibits proliferation as well as promotes metastasis of ccRCC cells. Mechanistically, IGF2BP2 systematically regulates TGF-ß-SMAD signaling family, including TGF-ß1/2, TGF-ßR1/2 and SMAD2/3/4, through mediating their mRNA stability in an m6A-dependent manner. Furthermore, the functional effects of IGF2BP2 on ccRCC cells is mediated by TGF-ß-SMAD signaling downstream effector SMAD4, which is identified three m6A sites in 5'UTR and CDS. Our study establishes IGF2BP2-TGF-ß-SMAD axis as a new regulatory effector in ccRCC, providing new insights for developing novel therapeutic strategies.


Assuntos
Adenosina , Carcinoma de Células Renais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Proteínas de Ligação a RNA , Transdução de Sinais , Proteínas Smad , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Linhagem Celular Tumoral , Proteínas Smad/metabolismo , Proteínas Smad/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Animais , Proteína Smad4/metabolismo , Proteína Smad4/genética , Camundongos , Movimento Celular , Estabilidade de RNA , Metástase Neoplásica
16.
JCO Clin Cancer Inform ; 8: e2400031, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39270146

RESUMO

PURPOSE: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT. METHODS: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O2·kg-1·min-1) and CRF response. RESULTS: Baseline CRF ranged from 10.2 to 38.8 mL O2·kg-1·min-1; CRF response ranged from -15.7 to 4.1 mL O2·kg-1·min-1. Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF (P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O2·kg-1·min-1 v 0.70 ± 2.22 mL O2·kg-1·min-1) was blunted in phenogroup 2 compared with phenogroup 1. CONCLUSION: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.


Assuntos
Neoplasias da Mama , Aptidão Cardiorrespiratória , Aprendizado de Máquina , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Terapia por Exercício/métodos , Exercício Físico , Idoso , Adulto
17.
Cancer Med ; 13(17): e70169, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39225546

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a prevalent and lethal tumor, with metastasis being the leading cause of mortality. Previous research has indicated that the long non-coding RNA (lncRNA) CCAT2 is involved in the regulation of various tumor progression mechanisms. However, the precise role of CCAT2 in CRC proliferation and metastasis remains ambiguous. This study seeks to elucidate the mechanisms through which CCAT2 influences CRC. METHODS: High-throughput sequencing and RT-qPCR were used to detect CCAT2 expression in CRC. Functional analyses including CCK8, colony formation, wound healing migration, transwell chamber, and Muse® Cell Analyzer assays were performed to study the effects of CCAT2 gene deletion on CRC cells. RNA-pulldown and protein mass spectrometry were employed to identify the interaction between CCAT2 and GNB2 protein. RESULTS: Increased CCAT2 expression was found in CRC, especially in metastatic CRC. Deletion of CCAT2 gene inhibited CRC cell proliferation, migration, and invasion while promoting apoptosis. The interaction between CCAT2 and GNB2 protein was shown to modulate GNB2 protein alterations and affect the ERK and Wnt signaling pathways, thereby promoting CRC proliferation and metastasis. CONCLUSION: CCAT2 plays a crucial role in CRC progression by modulating the ERK and Wnt signaling pathways through its interaction with GNB2. These findings highlight the importance of CCAT2 as a key regulatory element in the mechanisms underlying CRC proliferation and metastasis.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante , Via de Sinalização Wnt , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apoptose , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Sistema de Sinalização das MAP Quinases , Metástase Neoplásica , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
18.
Cell Death Dis ; 15(9): 654, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39231945

RESUMO

Transforming growth factor (TGF)-ß signaling is critical for epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis. Disruption of Smad-depednent TGF-ß signaling has been shown in CRC cells. However, TGF-ß receptor remains expressed on CRC cells. Here, we investigated whether the cooperation between tumor-associated N-glycosylation and a glycan-binding protein modulated the TGF-ß-driven signaling and metastasis of CRC. We showed that galectin-8, a galactose-binding lectin, hampered TGF-ß-induced EMT by interacting with the type II TGF-ß receptor and competing with TGF-ß binding. Depletion of galectin-8 promoted the migration of CRC cells by increasing TGF-ß-receptor-mediated RAS and Src signaling, which was attenuated after recombinant galectin-8 treatment. Treatment with recombinant galectin-8 also induces JNK-dependent apoptosis in CRC cells. The anti-migratory effect of galectin-8 depended on ß4-galactosyltransferase-I (B4GALT1), an enzyme involved in N-glycan synthesis. Increased B4GALT1 expression was observed in clinical CRC samples. Depletion of B4GALT1 reduced the metastatic potential of CRC cells. Furthermore, inducible expression of galectin-8 attenuated tumor development and metastasis of CRC cells in an intra-splenic injection model. Our results thus demonstrate that galectin-8 alters non-canonical TGF-ß response in CRC cells and suppresses CRC progression.


Assuntos
Movimento Celular , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Galactosiltransferases , Galectinas , Metástase Neoplásica , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Galectinas/metabolismo , Galectinas/genética , Galactosiltransferases/metabolismo , Galactosiltransferases/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Linhagem Celular Tumoral , Transdução de Sinais , Camundongos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Camundongos Nus , Ligação Proteica , Apoptose/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Camundongos Endogâmicos BALB C
19.
Funct Integr Genomics ; 24(5): 158, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39249547

RESUMO

Long non-coding RNAs (lncRNAs) regulate the occurrence, development and progression of oral squamous cell carcinoma (OSCC). We elucidated the expression features of MAGEA4-AS1 in patients with OSCC and its activity as an OSCC biomarker. Furthermore, the impact of up-regulation of MAGEA4-AS1 on the cellular behaviors (proliferation, migration and invasion) of OSCC cells and intrinsic signal mechanisms were evaluated. Firstly, we analyzed MAGEA4-AS1 expression data in The Cancer Genome Atlas (TCGA) OSCC using a bioinformatics approach and in 45 pairs of OSCC tissues using qPCR. Then CCK-8, ethynyl deoxyuridine, colony formation, transwell and wound healing assays were conducted to assess changes in the cell proliferation, migration and invasion protential of shMAGEA4-AS1 HSC3 and CAL27 cells. The RNA sequence of MAGEA4-AS1 was identified using the rapid amplification of cDNA ends (RACE) assay. And whole-transcriptome sequencing was used to identify MAGEA4-AS1 affected genes. Additionally, dual-luciferase reporter system, RNA-binding protein immunoprecipitation (RIP), and rescue experiments were performed to clarify the role of the MAGEA4-AS1-p53-MK2 signaling pathway. As results, we found MAGEA4-AS1 was up-regulated in OSCC tissues. We identified a 418 nucleotides length of the MAGEA4-AS1 transcript and it primarily located in the cell nucleus. MAGEA4-AS1 stable knockdown weakened the proliferation, migration and invasion abilities of OSCC cells. Mechanistically, p53 protein was capable to activate MK2 gene transcription. RIP assay revealed an interaction between p53 and MAGEA4-AS1. MK2 up-regulation in MAGEA4-AS1 down-regulated OSCC cells restored MK2 and epithelial-to-mesenchymal transition related proteins' expression levels. In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.


Assuntos
Movimento Celular , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Bucais , Proteínas Serina-Treonina Quinases , RNA Longo não Codificante , Transdução de Sinais , Proteína Supressora de Tumor p53 , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Metástase Neoplásica
20.
Nat Commun ; 15(1): 7885, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251588

RESUMO

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution.


Assuntos
Acrilamidas , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Interleucina-6 , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Fator de Transcrição STAT3 , Humanos , Glicosilação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Interleucina-6/metabolismo , Interleucina-6/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Inibidores de Proteínas Quinases/farmacologia , Animais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Linhagem Celular Tumoral , Acrilamidas/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Compostos de Anilina/farmacologia , Receptor gp130 de Citocina/metabolismo , Receptor gp130 de Citocina/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB1/genética , Fosforilação , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quinases da Família src/metabolismo , Quinases da Família src/genética , Camundongos Nus , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Metástase Neoplásica , Regulação Neoplásica da Expressão Gênica , Feminino , Indóis , Pirimidinas
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