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The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/ß-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.
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Fluoruracila/farmacologia , Glipicanas/metabolismo , Neoplasias Pancreáticas/metabolismo , beta Catenina/metabolismo , Western Blotting , Linhagem Celular Tumoral , Biologia Computacional , Glipicanas/genética , Humanos , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , beta Catenina/genéticaRESUMO
BACKGROUND/AIMS: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. METHODS: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. RESULTS: SFN can inhibit pancreatic cancer cell growthï¼ promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. CONCLUSION: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.
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Anticarcinógenos/farmacologia , Glucose/farmacologia , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anticarcinógenos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Isotiocianatos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , SulfóxidosRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer. METHODS: LSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein. RESULTS: Following metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson's trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival. CONCLUSIONS: Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.
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Carcinogênese/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Carcinogênese/metabolismo , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Queratina-19/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Transgênicos , Pâncreas/efeitos dos fármacos , Ductos Pancreáticos/efeitos dos fármacos , Ductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/metabolismoRESUMO
Hypoxia can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, their mechanisms remain unclear. The objective of this study was to evaluate the role of Gli-1, an effector of the Hedgehog pathway, in the hypoxia-induced EMT and invasion of breast cancer cells. Human breast cancer MDA-MB-231 cells were transfected with HIF-1α or Gli-1-specific small interfering RNA (siRNA) and cultured under a normoxic or hypoxic condition. The relative levels of HIF-1α, Gli-1, E-cadherin, and vimentin in the cells were characterized by quantitative RT-PCR and Western blot assays, and the invasion of MDA-MB-231 cells was determined. Data was analyzed by Student T test, one-way ANOVA, and post hoc LSD test or Mann-Whitney U when applicable. We observed that hypoxia significantly upregulated the relative levels of vimentin expression, but downregulated E-cadherin expression and promoted the invasion of MDA-MB-231 cells, associated with upregulated HIF-1α translation and Gil-1 expression. Knockdown of HIF-1α mitigated hypoxia-modulated Gil-1, vimentin and E-cadherin expression, and invasion of MDA-MB-231 cells. Knockdown of Gil-1 did not significantly change hypoxia-upregulated HIF-1α translation but completely eliminated hypoxia-modulated vimentin and E-cadherin expression and invasion of MDA-MB-231 cells. These data indicate that Gil-1 is crucial for hypoxia-induced EMT and invasion of breast cancer cells and may be a therapeutic target for intervention of breast cancer metastasis.
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Neoplasias da Mama/genética , Hipóxia Celular/genética , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição/biossíntese , Neoplasias da Mama/patologia , Caderinas/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Invasividade Neoplásica/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Vimentina/biossíntese , Proteína GLI1 em Dedos de ZincoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a type of highly lethal malignant tumor. PDAC is locally invasive and is surrounded by a dense desmoplasia or fibrosis, which can involve adjacent vital structures. Previously, the effect of pancreatic stellate cells (PSCs) of stroma in the progression of PDAC has received more attention, and most in vitro and in vivo studies revealed that PSCs appear to confer biological aggressiveness. However, clinical trials targeting desmoplasia or PSCs showed disappointing results. Recent studies found that stromal components, especially activated PSCs, are able to inhibit the occurrence and progression of PDAC. Inhibition of the stroma or desmoplasia through genetic regulations or drugs accelerates the formation and progression of PDAC. Thus, we hypothesized that in various times and spaces, there is a balance between the tumor epithelia and stroma; once the balance is upset, the tumor traits may undergo certain changes. Therefore, finding the key changing points of this relationship to corrupt or influence it, instead of blindly inhibiting the stroma motivation or simply maintaining stroma activation, will destroy the cooperation or promote the competition and antagonism among cells. This approach may render tumors more vulnerable and thus unable to resist anti-cancer therapies.
Assuntos
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Carcinoma Ductal Pancreático/patologia , Ensaios Clínicos como Assunto , Células Epiteliais/patologia , Humanos , Neoplasias Pancreáticas/patologia , Células Estromais/patologiaRESUMO
BACKGROUND: Hypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion. METHODS: Pancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay. RESULTS: Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA. In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-ß, KRAS or RTK) bypassing SMO to activate GLI1 directly. CONCLUSIONS: Our findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.
Assuntos
Transição Epitelial-Mesenquimal , Proteínas Hedgehog/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Hipóxia Celular , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Inativação Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ligantes , Modelos Biológicos , Invasividade Neoplásica , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Neoplasias Pancreáticas/genética , Fenótipo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Transativadores/genética , Transativadores/metabolismo , Proteína GLI1 em Dedos de ZincoRESUMO
Tuft cells are solitary chemosensory cells distributed mainly in hollow organs and detected in human and mouse pancreas precursor lesions of pancreatic cancer. Induced by inflammation and KRAS mutation, pancreatic acinar cell-derived tuft cells play a protective role in epithelium injury. The tumour suppression of tuft cells has been indicated in some studies. However, the function of tuft cells in pancreatic cancer remains unclear. In this review, we first introduce the definition of tuft cells and then review the relationship between tuft cells and pancreatic inflammation. In addition, we emphasized the role of tuft cells in the genesis and development of pancreatic cancers, especially the part of markers for tuft cell's doublecortin-like kinase 1 (DCLK1). Finally, we turn to the microscopic perspective and review the interactions between tuft cells and the microbiome in the pancreatic microenvironment. Overall, we describe the role of tuft cells in response to tissue damage and tumour progression in the pancreas. Nevertheless, the specific formation principle and the more detailed mechanism of action of tuft cells in the pancreas remain to be further explored.
Assuntos
Pâncreas , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Pâncreas/patologia , Proteínas Serina-Treonina Quinases/genética , Neoplasias Pancreáticas/patologia , Inflamação/patologia , Microambiente Tumoral , Quinases Semelhantes a Duplacortina , Neoplasias PancreáticasRESUMO
Following the publication of the above article, a concerned reader drew to the Editor's attention that there were a number of apparent anomalies associated with the western blots featured in Figs. 1C and E, 3A, C and E, 4A, C and E, 5B, 8A and C; moreover, the images shown for the immunohistochemical experiments in Fig. 8E contained groupings of cells that were markedly similar in appearance, comparing across the eight separate figure parts. After having conducted an internal investigation of the data in this paper, the Editor of International Journal of Molecular Medicine has judged that the potentially anomalous presentation of the western blotting data and the strikingly similar groupings of cells in Fig. 8E were too extensive that these features could have been attributed to pure coincidence. Therefore, the Editor has decided that this article should be retracted from the publication on the grounds of an overall lack of confidence in the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor sincerely apologizes to the readership for any incovenience caused, and we thank the reader for bringing this matter to our attention. [International Journal of Molecular Medicine 35: 653663, 2015; DOI: 10.3892/ijmm.2014.2055].
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Activation of the hedgehog (Hh) signaling pathway is involved in embryo development and tumorigenesis. While normal pancreatic tissue exhibits little Hh pathway activity, patients with pancreatic adenocarcinoma have high levels of Hh pathway signaling in both the tumor epithelia and the surrounding stromal tissue. Hh ligands expressed by pancreatic cancers promote tumor growth indirectly by activating Hh signaling in the surrounding stroma. This paracrine activation of Hh signaling in the tumor microenvironment provides a more favorable environment for tumor cellular proliferation, metastasis, and resistance to therapy. Taken together, these findings are of valuable implications for the use of Hh pathway inhibitors currently in development and inhibition of the Hh pathway paracrine loop in pancreatic cancer.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Comunicação Parácrina , Microambiente Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Metástase Neoplásica , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Plasticidade Neuronal , GencitabinaRESUMO
As one of the best-studied long noncoding RNAs, nuclear paraspeckle assembly transcript 1 (NEAT1) plays a pivotal role in the progression of cancers. NEAT1, especially its isoform NEAT1-1, facilitates the growth and metastasis of various cancers, excluding acute promyelocytic leukemia. NEAT1 can be elevated via transcriptional activation or stability alteration in cancers changing the aggressive phenotype of cancer cells. NEAT1 can also be secreted from other cells and be delivered to cancer cells through exosomes. Hence, elucidating the molecular interaction of NEAT1 may shed light on the future treatment of cancer. Herein, we review the molecular function of NEAT1 in cancer progression, and explain how NEAT1 interacts with RNAs, proteins, and DNA promoter regions to upregulate tumorigenic factors.
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Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.
Assuntos
Fator de Crescimento Neural , Neoplasias Pancreáticas , Movimento Celular , Fator de Crescimento de Hepatócito , Humanos , Invasividade Neoplásica/patologia , Fator de Crescimento Neural/metabolismo , Neoplasias Pancreáticas/patologia , Serina-Treonina Quinases TOR , Neoplasias PancreáticasRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death. A growing number of studies believe that matrix stiffness plays an important role in the development of pancreatic disease. As one of the famous mechanically activated cation channels, Piezo1 has received more attention recently. Here we tried to describe the role of Piezo1 on PDAC progression. It seemed that Piezo1 was a potential tumor-promoting marker of pancreatic cancer. By using Yoda1, we measured the intracellular calcium flux mediated by Piezo1 which confirmed it did act as an intrinsic cation channel in pancreatic cancer cells. Additionally, we also found the inhibition of Piezo1 could inhibit cancer progression in vitro; however, Piezo1 activation (induced by Yoda1) had an oppositive effect. Moreover, Piezo1 activation may also accelerate pancreatic cancer tumor growth/formation via modulating pancreatic cancer cell-tumor microenvironment interactions in vivo. We concluded that Piezo1 acted as an oncogenic gene in pancreatic cancer progression. It might be one of promising targets for pancreatic cancer therapy.
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Canais Iônicos , Neoplasias Pancreáticas , Humanos , Mecanotransdução Celular/fisiologia , Pâncreas/metabolismo , Hormônios Pancreáticos , Oncogenes/genética , Neoplasias Pancreáticas/genética , Microambiente TumoralRESUMO
Emerging evidence suggests that ADP-ribosylation factor like-4c (Arl4c) may be a potential choice for cancer treatment. However, its role in pancreatic cancer, especially in tumor-stroma interactions and drug resistance, is still unknown. In the current study, we examined the proliferation and drug resistance effect of Arl4c on pancreatic cancer cells. Furthermore, we explored the contribution of Arl4c high expression in pancreatic stellate cell (PSC) activation. We found that high Arl4c expression is associated with cell proliferation, drug resistance, and PSC activation. In detail, Arl4c regulates connective tissue growth factor (CTGF) paracrine, further induces autophagic flux in PSCs, resulting in PSC activation. TGFß1 secreted by activated PSCs enhances cancer cell stem cell properties via smad2 signaling, further increasing cell drug resistance. YAP is an important mediator of the Arl4c-CTGF loop. Taken together, these results suggest that Arl4c is essential for pancreatic cancer progression and may be an effective therapeutic choice.
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. METHODS: The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR). RESULTS: In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro. CONCLUSION: Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.
Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Receptores ErbB/metabolismo , Animais , Carcinogênese , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos TransgênicosRESUMO
Resveratrol is a natural polyphenolic compound with multiple biological effects, e.g., proliferation inhibition, anti-oxidation, and neuroprotection. Besides that, studies have shown that resveratrol inhibits tumor growth and migration, as well as epithelial-mesenchymal transition (EMT). However, its molecular mechanisms in tumor progression are not fully understood. Nutrient-deprivation autophagy factor-1 (NAF-1) is mainly found in the endoplasmic reticulum and mitochondrial outer membrane. It is an important genetic locus for regulating oxidative stress and autophagy. The molecular mechanism of NAF-1 in pancreatic cancer is currently unclear. The current study found that NAF-1 is expressed in pancreatic cancer tissue and correlated with the progression of pancreatic cancer. Furthermore, we found that NAF-1 inhibition significantly inhibits the stem cell characteristics and the invasion and migration abilities of pancreatic cancer cells. In a subcutaneous xenograft model of pancreatic cancer in nude mice, resveratrol inhibited the expression of NAF-1, thereby inhibiting tumor growth. Taken together, resveratrol could be an effective anti-tumor drug, and NAF-1 may be a rational therapeutic target.
RESUMO
Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial-mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor-microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antioxidantes/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Células Estreladas do Pâncreas/efeitos dos fármacos , Resveratrol/uso terapêutico , Adenocarcinoma/patologia , Antioxidantes/farmacologia , Carcinoma Ductal Pancreático/patologia , Progressão da Doença , Humanos , Resveratrol/farmacologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumour with an extremely poor prognosis due to its insidious initiation and a lack of therapeutic strategies. Resveratrol suppresses pancreatic cancer progression and attenuates pancreatitis by modulating multiple targets, including nuclear factor kappa B (NFκB) signalling pathways. However, the effect of resveratrol on pancreatic cancer initiation and its mechanisms remain unclear. In this study, we utilised the LSL-KrasG12D/+; Pdx1-Cre (KC) spontaneous pancreatic precancerous lesion mouse model to explore the anti-tumourigenesis mechanisms of resveratrol in vivo. In vitro acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasias (PanINs) formation assays were performed by pancreatic acinar cell 3-dimensional (3D) culture. Histopathological analysis was used to examine the pathological morphology of pancreatic tissues. Resveratrol prevented the progression of pancreatic precancerous lesions and inhibited the activation of NFκB signalling pathway-related molecules in KC mouse pancreatic tissues. In addition, resveratrol reduced the severity of cerulein-induced pancreatitis and the formation of ADM/PanINs in vivo and in vitro, which may be related to its effect on NFκB inactivation. Furthermore, pancreatic acinar 3D culture demonstrated that activation of the NFκB signalling pathway promoted the formation of ADM/PanINs in vitro, and this initiating effect of NFκB was blocked by resveratrol. Resveratrol slowed the tumourigenesis of pancreatic cancer by inhibiting NFκB activation.
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Carcinogênese/efeitos dos fármacos , Carcinoma Ductal Pancreático/prevenção & controle , NF-kappa B/metabolismo , Resveratrol/farmacologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Células Cultivadas , Ceruletídeo/farmacologia , Proteínas de Homeodomínio/genética , Metaplasia/prevenção & controle , Camundongos , Camundongos Transgênicos , Pancreatite/patologia , Pancreatite/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Transativadores/genéticaRESUMO
Resveratrol is a type of polyphenol that is abundantly present in knotweed and grapes, and has been confirmed to have tumorinhibitory properties. However, the effect of resveratrol on tumor cells under chronic stress conditions remains unclear. The aim of the present study was to demonstrate that resveratrol exerts a significant inhibitory effect on the growth and proliferation of tumor cells under chronic stress in a dosedependent manner. Furthermore, resveratrol was able to induce apoptosis of cancer cells under chronic stress conditions. Moreover, resveratrol was found to inhibit tumor cells under chronic stress by decreasing the expression of the ß2adrenergic receptor (ADRB2); in addition, the protein expression of hypoxiainducible factor (HIF)1α was suppressed by resveratrol in a dosedependent manner. Thus, these data suggest that resveratrol inhibits the growth of cancer cells under chronic stress by regulating the ADRB2HIF1α axis. In summary, the present study may provide a new basis supporting the use of resveratrol for the prevention and treatment of pancreatic cancer.
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Antineoplásicos Fitogênicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/tratamento farmacológico , Receptores Adrenérgicos beta 2/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias/patologia , Resveratrol/uso terapêuticoRESUMO
Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1α (HIF-1α) expression to promote angiogenesis, epithelial to mesenchymal transition (EMT) process and invasion. And HSCs could secrete soluble factors, such as interleukin-6 (IL-6), vascular endothelial cell growth factor (VEGF), and stromal-derived factor-1 (SDF-1) to facilitate HCC progression. Curcumin could significantly suppress the above HSC-induced effects in HCC and could abrogate ROS and HIF-1α expression in HCC. HIF-1α or connective tissue growth factor (CTGF) knockdown could abolish the aforementioned curcumin affection. Moreover, CTGF is a downstream gene of HIF-1α. In addition, nuclear factor E2-related factor 2 (Nrf2) and glutathione (GSH) are involved in curcumin protection of HCC. These data indicate that curcumin may induce ROS scavenging by upregulating Nrf2 and GSH, thus inhibiting HIF-1α stabilization to suppress CTGF expression to exhibit its protection on HCC. Curcumin has a promising therapeutic effect on HCC. CTGF is responsible for curcumin-induced protection in HCC.