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1.
Clin Exp Med ; 24(1): 219, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39261380

RESUMEN

Resistance to immunotherapy poses a significant challenge in the treatment of colorectal cancer (CRC), and the underlying mechanisms are not fully understood. Recent studies have implicated PFKFB3, a crucial glycolytic enzyme, in shaping the tumor microenvironment in CRC. Our study aimed to systematically study the role of PFKFB3 in CRC. Bioinformatic analysis revealed that PFKFB3 expression is notably elevated in CRC tissues compared to normal counterparts. In vivo experiments confirmed that suppressing PFKFB3 reduces the tumorigenesis of CRC. We identified multiple cancer-associated pathways positively correlated with high expression of PFKFB3, such as epithelial-mesenchymal transition (EMT), hypoxia, KRAS signaling, angiogenesis, PI3K/AKT/mTOR, Hedgehog, and Notch pathways. Additionally, PFKFB3 exhibited significant correlations with various immune-related pathways, including complement, IL-2/STAT5, IL-6/JAK/STAT3, IFN-α/IFN-γ, TGF-ß, and TNF-α/NF-κB, as well as several immunosuppressive cell markers found in regulatory T cells (CCR8, TGFB1, STAT5B, FOXP3), M2 macrophages (CD163, VSIG4, MS4A4A), T cell exhaustion markers (CTLA-4, PDCD1, LAG3), and PD-L1. Intriguingly, increased PFKFB3 expression was observed in PD-L1 blockade-resistant patients and was associated with shorter overall survival. In a nutshell, PFKFB3 plays an important role in CRC tumorigenesis and resistance to immunotherapy. Targeting PFKFB3 inhibits tumor formation and enhances the efficacy of immunotherapy. Our findings underscore the functions of PFKFB3 in CRC, shedding light on both cancer-related and immunosuppressive pathways.


Asunto(s)
Neoplasias Colorrectales , Resistencia a Antineoplásicos , Inmunoterapia , Fosfofructoquinasa-2 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismo , Humanos , Inmunoterapia/métodos , Animales , Microambiente Tumoral , Ratones , Masculino , Femenino , Línea Celular Tumoral , Transducción de Señal , Regulación Neoplásica de la Expresión Génica
2.
J Natl Cancer Cent ; 4(1): 25-35, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-39036388

RESUMEN

Hepatic stellate cells (HSCs), a distinct category of non-parenchymal cells in the liver, are critical for liver homeostasis. In healthy livers, HSCs remain non-proliferative and quiescent. However, under conditions of acute or chronic liver damage, HSCs are activated and participate in the progression and regulation of liver diseases such as liver fibrosis, cirrhosis, and liver cancer. Fatty liver diseases (FLD), including nonalcoholic (NAFLD) and alcohol-related (ALD), are common chronic inflammatory conditions of the liver. These diseases, often resulting from multiple metabolic disorders, can progress through a sequence of inflammation, fibrosis, and ultimately, cancer. In this review, we focused on the activation and regulatory mechanism of HSCs in the context of FLD. We summarized the molecular pathways of activated HSCs (aHSCs) in mediating FLD and their role in promoting liver tumor development from the perspectives of cell proliferation, invasion, metastasis, angiogenesis, immunosuppression, and chemo-resistance. We aimed to offer an in-depth discussion on the reciprocal regulatory interactions between FLD and HSC activation, providing new insights for researchers in this field.

3.
Proc Natl Acad Sci U S A ; 121(11): e2307802121, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38437557

RESUMEN

RNA interference (RNAi) therapeutics are an emerging class of medicines that selectively target mRNA transcripts to silence protein production and combat disease. Despite the recent progress, a generalizable approach for monitoring the efficacy of RNAi therapeutics without invasive biopsy remains a challenge. Here, we describe the development of a self-reporting, theranostic nanoparticle that delivers siRNA to silence a protein that drives cancer progression while also monitoring the functional activity of its downstream targets. Our therapeutic target is the transcription factor SMARCE1, which was previously identified as a key driver of invasion in early-stage breast cancer. Using a doxycycline-inducible shRNA knockdown in OVCAR8 ovarian cancer cells both in vitro and in vivo, we demonstrate that SMARCE1 is a master regulator of genes encoding proinvasive proteases in a model of human ovarian cancer. We additionally map the peptide cleavage profiles of SMARCE1-regulated proteases so as to design a readout for downstream enzymatic activity. To demonstrate the therapeutic and diagnostic potential of our approach, we engineered self-assembled layer-by-layer nanoparticles that can encapsulate nucleic acid cargo and be decorated with peptide substrates that release a urinary reporter upon exposure to SMARCE1-related proteases. In an orthotopic ovarian cancer xenograft model, theranostic nanoparticles were able to knockdown SMARCE1 which was in turn reported through a reduction in protease-activated urinary reporters. These LBL nanoparticles both silence gene products by delivering siRNA and noninvasively report on downstream target activity by delivering synthetic biomarkers to sites of disease, enabling dose-finding studies as well as longitudinal assessments of efficacy.


Asunto(s)
Neoplasias Ováricas , Péptidos , Humanos , Femenino , Interferencia de ARN , Péptidos/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Péptido Hidrolasas , ARN Interferente Pequeño/genética , Endopeptidasas , Proteínas Cromosómicas no Histona , Proteínas de Unión al ADN
5.
Nat Metab ; 5(10): 1642-1645, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37794202
6.
J Cell Mol Med ; 27(16): 2372-2384, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400979

RESUMEN

Metastasis is the primary cause of death of hepatocellular carcinoma (HCC), while the mechanism underlying this severe disease remains largely unclear. The Kruppel-like factor (KLF) family is one of the largest transcription factor families that control multiple physiologic and pathologic processes by governing the cellular transcriptome. To identify metastatic regulators of HCC, we conducted gene expression profiling on the MHCC97 cell series, a set of subclones of the original MHCC97 that was established by in vivo metastasis selection therefore harbouring differential metastatic capacities. We found that the expression of KLF9, a member of the KLF family, was dramatically repressed in the metastatic progeny clone of the MHCC97 cells. Functional studies revealed overexpression of KLF9 suppressed HCC migration in vitro and metastasis in vivo, while knockdown of KLF9 was sufficient to promote cell migration and metastasis accordingly. Mechanistically, we found the expression of KLF9 can reverse the pro-metastatic epithelial-mesenchymal transition (EMT) program via direct binding to the promoter regions of essential mesenchymal genes, thus repressing their expression. Interestingly, we further revealed that KLF9 was, in turn, directly suppressed by a mesenchymal transcription factor Slug, suggesting an intriguing negative feedback loop between KLF9 and the EMT program. Using clinical samples, we found that KLF9 was not only downregulated in HCC tissue compared to its normal counterparts but also further reduced in the HCC samples of whom had developed metastatic lesions. Together, we established a critical transcription factor that represses HCC metastasis, which is clinically and mechanically significant in HCC therapies.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción/metabolismo
7.
Life Sci Alliance ; 6(1)2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36375842

RESUMEN

Epithelial-mesenchymal transition (EMT) is a cellular mechanism used by cancer cells to acquire migratory and stemness properties. In this study, we show, through in vitro, in vivo, and 3D culture experiments, that the mitochondrial protein LACTB manifests tumor suppressor properties in ovarian cancer. We show that LACTB is significantly down-regulated in epithelial ovarian cancer cells and clinical tissues. Re-expression of LACTB negatively effects the growth of cancer cells but not of non-tumorigenic cells. Mechanistically, we show that LACTB leads to differentiation of ovarian cancer cells and loss of their stemness properties, which is achieved through the inhibition of the EMT program and the LACTB-dependent down-regulation of Snail2/Slug transcription factor. This study uncovers a novel role of LACTB in ovarian cancer and proposes new ways of counteracting the oncogenic EMT program in this model system.


Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Ováricas , Factores de Transcripción de la Familia Snail , beta-Lactamasas , Femenino , Humanos , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Carcinogénesis , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo
8.
Cell Rep ; 40(9): 111295, 2022 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-36044847

RESUMEN

More than 40% of patients with late-stage colorectal cancer (CRC) develop liver metastasis (LM). Which immune cells play important roles in CRC-LM and contribute to the difference between left-sided CRC (LCC) and right-sided CRC (RCC) remain unclear. By single-cell RNA sequencing (scRNA-seq), we not only find that activated B cells are significantly depleted in CRC with LM, but also find a subtype of B cells developed from activated B cells, namely immature plasma cell population alpha (iMPA), highly correlated with metastasis. Mechanistically, inhibition of the Wnt and transforming growth factor ß (TGF-ß) pathways in cancer cell promotes activated B cell migration via the SDF-1-CXCR4 axis. This study reveals that B cell subpopulations in the tumor immune microenvironment (TIME) play a key role in CRC-LM as well as in LCC and RCC. The preventive effects of modulating B cell subpopulations in CRC may provide a rationale for subsequent drug development and CRC-LM management.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Colorrectales , Neoplasias Renales , Neoplasias Hepáticas , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral
10.
Nat Metab ; 4(2): 239-253, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35145325

RESUMEN

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Glutamato-Amoníaco Ligasa , Humanos , Ratones , Mitosis
11.
Nat Commun ; 12(1): 7116, 2021 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-34893587

RESUMEN

Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in stromal tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and function. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through a collagen receptor. Discoidin domain receptor tyrosine kinase 1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells via Notch signaling to differentiate and form lobules. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that lead to formation of a complex ductal-lobular network.


Asunto(s)
Mama/citología , Mama/fisiología , Comunicación Celular/fisiología , Diferenciación Celular/fisiología , Receptor con Dominio Discoidina 1/metabolismo , Materiales Biocompatibles , Ingeniería Biomédica , Línea Celular , Receptor con Dominio Discoidina 1/genética , Células Epiteliales/citología , Matriz Extracelular , Humanos , Regeneración , Transducción de Señal , Células Madre/citología
12.
Front Oncol ; 11: 770843, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34746012

RESUMEN

As a central cellular program to sense and transduce stress signals, the integrated stress response (ISR) pathway has been implicated in cancer initiation and progression. Depending on the genetic mutation landscape, cellular context, and differentiation states, there are emerging pieces of evidence showing that blockage of the ISR can selectively and effectively shift the balance of cancer cells toward apoptosis, rendering the ISR a promising target in cancer therapy. Going beyond its pro-survival functions, the ISR can also influence metastasis, especially via proteostasis-independent mechanisms. In particular, ISR can modulate metastasis via transcriptional reprogramming, in the help of essential transcription factors. In this review, we summarized the current understandings of ISR in cancer metastasis from the perspective of transcriptional regulation.

13.
Oncogene ; 40(16): 2982-2997, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33767438

RESUMEN

Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to a lack of well-defined molecular targets. The Wnt/ß-catenin pathway is known to be activated in many TNBC patients and BCL9 and BCL9L are important transcriptional co-activators of ß-catenin, but whether inhibition of BCL9/BCL9L can suppress TNBC growth and the underlying mechanism are not fully understood. Here we demonstrate that the expression of BCL9 and BCL9L is directly correlated with malignancy in TNBC patient tumors and that BCL9 and BCL9L promote tumor cell growth, cell migration and metastasis in TNBC models. Mechanistically, we found that BCL9/BCL9L promotes tumorigenicity through both the Wnt and TGF-ß pathways. Besides, BCL9/BCL9L expression inversely correlates with CD8+ T cell infiltration in TNBC and BCL9/BCL9L inhibits the infiltration of CD8+ T cells in the tumor microenvironment. hsBCL9CT-24, an inhibitor of BCL9/ß-catenin peptides, promotes intratumoral infiltration of cytotoxic T cells, reducing regulatory T cells (Treg) and increasing dendritic cells (DCs). Inhibition of BCL9/BCL9L and TGF-ß suppresses activity of Treg. TGF-ß signaling increases tumor infiltration of cytotoxic CD8+ T cells. In accordance, genetic or pharmacological inhibition of BCL9/BCL9L synergizes with PD-1/L1 antibodies to inhibit tumor growth. In summary, these results suggest that targeting BCL9/BCL9L has a direct anti-tumor effect and also unleashes an anti-cancer immune response through inhibition of both Wnt and TGF-ß signaling, suggesting a viable therapeutic approach for TNBC treatment.


Asunto(s)
Proteínas de Unión al ADN/inmunología , Factores de Transcripción/inmunología , Neoplasias de la Mama Triple Negativas/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/fisiología , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral
14.
Cell Prolif ; 52(3): e12583, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30793395

RESUMEN

OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of ß-catenin to the nucleus by activating glycogen synthase kinase-3ß (GSK3ß). Moreover, constitutively active ß-catenin blocked the suppressive effects of WISP3 on HCC. CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of ß-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.


Asunto(s)
Proteínas CCN de Señalización Intercelular/genética , Proteínas CCN de Señalización Intercelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Transporte Activo de Núcleo Celular , Animales , Proteínas CCN de Señalización Intercelular/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Factores de Transcripción TCF/metabolismo , beta Catenina/metabolismo
15.
Br J Cancer ; 118(10): 1337-1348, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29717200

RESUMEN

BACKGROUND: Chemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown. METHODS: Chemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin. RESULTS: Chemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN-CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo. CONCLUSIONS: Our study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Quimiocinas/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Fosfohidrolasa PTEN/genética , Receptores de Quimiocina/genética , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Movimiento Celular , Proliferación Celular , Quimiocinas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Proteína Oncogénica v-akt/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Hepatology ; 68(2): 533-546, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29506314

RESUMEN

Obesity is associated with both endoplasmic reticulum (ER) stress and chronic metabolic inflammation. ER stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). It is unclear whether individual UPR pathways are mechanistically linked to HCC development, however. Here we report a dual role for inositol-requiring enzyme 1α (IRE1α), the ER-localized UPR signal transducer, in obesity-promoted HCC development. We found that genetic ablation of IRE1α in hepatocytes not only markedly reduced the occurrence of diethylnitrosamine (DEN)-induced HCC in liver-specific IRE1α knockout (LKO) mice when fed a normal chow (NC) diet, but also protected against the acceleration of HCC progression during high-fat diet (HFD) feeding. Irrespective of their adiposity states, LKO mice showed decreased hepatocyte proliferation and signal transducer and activator of transcription 3 (STAT3) activation, even in the face of increased hepatic apoptosis. Furthermore, IRE1α abrogation blunted obesity-associated activation of hepatic inhibitor of nuclear factor kappa B kinase subunit beta (IKKß)-nuclear factor kappa B (NF-κB) pathway, leading to reduced production of the tumor-promoting inflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). Importantly, higher IRE1α expression along with elevated STAT3 phosphorylation was also observed in the tumor tissues from human HCC patients, correlating with their poorer survival rate. CONCLUSION: IRE1α acts in a feed-forward loop during obesity-induced metabolic inflammation to promote HCC development through STAT3-mediated hepatocyte proliferation. (Hepatology 2018).


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Endorribonucleasas/metabolismo , Neoplasias Hepáticas/metabolismo , Obesidad/complicaciones , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Proliferación Celular , Citocinas/metabolismo , Dieta Alta en Grasa , Dietilnitrosamina/farmacología , Hepatocitos/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Obesidad/veterinaria , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
17.
Nat Commun ; 8(1): 1079, 2017 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-29057869

RESUMEN

PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Unfortunately, chemical inhibitors of PERK's kinase activity cause on-target side effects that have precluded their further development. One strategy for resolving this difficulty would be to target downstream components of the pathway that specifically mediate PERK's pro-invasive and metastatic functions. Here we identify the transcription factor CREB3L1 as an essential mediator of PERK's pro-metastatic functions in breast cancer. CREB3L1 acts downstream of PERK, specifically in the mesenchymal subtype of triple-negative tumors, and its inhibition by genetic or pharmacological methods suppresses cancer cell invasion and metastasis. In patients with this tumor subtype, CREB3L1 expression is predictive of distant metastasis. These findings establish CREB3L1 as a key downstream mediator of PERK-driven metastasis and a druggable target for breast cancer therapy.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal/fisiología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Silenciador del Gen/fisiología , Humanos , Metástasis de la Neoplasia/genética , Proteínas del Tejido Nervioso/genética , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética
18.
Proc Natl Acad Sci U S A ; 114(16): 4153-4158, 2017 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-28377514

RESUMEN

Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.


Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Movimiento Celular , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Recurrencia Local de Neoplasia/patología , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Blood ; 128(23): 2637-2641, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27777239

RESUMEN

Burst-forming unit erythroid progenitors (BFU-Es) are so named based on their ability to generate in methylcellulose culture large colonies of erythroid cells that consist of "bursts" of smaller erythroid colonies derived from the later colony-forming unit erythroid progenitor erythropoietin (Epo)-dependent progenitors. "Early" BFU-E cells forming large BFU-E colonies presumably have higher capacities for self-renewal than do "late" BFU-Es forming small colonies, but the mechanism underlying this heterogeneity remains unknown. We show that the type III transforming growth factor ß (TGF-ß) receptor (TßRIII) is a marker that distinguishes early and late BFU-Es. Transient elevation of TßRIII expression promotes TGF-ß signaling during the early BFU-E to late BFU-E transition. Blocking TGF-ß signaling using a receptor kinase inhibitor increases early BFU-E cell self-renewal and total erythroblast production, suggesting the usefulness of this type of drug in treating Epo-unresponsive anemias.


Asunto(s)
Antígenos de Diferenciación/metabolismo , Eritrocitos/metabolismo , Células Precursoras Eritroides/metabolismo , Proteoglicanos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Anemia/metabolismo , Anemia/terapia , Animales , Eritrocitos/citología , Células Precursoras Eritroides/citología , Eritropoyetina/metabolismo , Humanos , Ratones
20.
Sci Rep ; 6: 25183, 2016 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-27174710

RESUMEN

Cancer stem-like cells (CSCs) play a key role in maintaining the aggressiveness of hepatocellular carcinoma (HCC), but the cell-biological regulation of CSCs is unclear. In the study, we report that thyroid hormone (TH) promotes cell self-renewal in HCC cells. TH also increases the percentage of CD90 + HCC cells and promotes drug resistance of HCC cells. By analyzing primary human HCC samples, we found that TRα transcript level is significantly elevated in primary liver cancer and portal vein metastatic tumor, compared to that of adjacent normal liver tissue. Knocking down TRα not only inhibits HCC self-renewal in vitro but also suppresses HCC tumor growth in vivo. Interestingly, treatment of TH leads to activation of NF-κB, which is required for the function of TH on inducing HCC cell self-renewal. We also found TRα and p65 cooperatively drive the expression of BMI1 by co-binding to the promoter region of BMI1 gene. In summary, our study uncovers a novel function of TH signaling in regulating the CSCs of HCC, and these findings might be useful for developing novel therapies by targeting TH function in HCC cells.


Asunto(s)
Carcinoma Hepatocelular/patología , Autorrenovación de las Células/efectos de los fármacos , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/fisiología , Hormonas Tiroideas/metabolismo , Humanos , FN-kappa B/metabolismo , Transducción de Señal , Receptores alfa de Hormona Tiroidea/metabolismo , Células Tumorales Cultivadas
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