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The incidence of hepatocellular carcinoma (HCC) has continued to increase annually worldwide, and HCC has become a common cause of cancer-related death. Despite great progress in understanding the molecular mechanisms underlying HCC development, the treatment of HCC remains a considerable challenge. Thus, the survival and prognosis of HCC patients remain extremely poor. In recent years, the role of ion channels in the pathogenesis of diseases has become a hot topic. In normal liver tissue, ion channels and transporters maintain water and electrolyte balance and acidâbase homeostasis. However, dysfunction of these ion channels and transporters can lead to the development and progression of HCC, and thus these ion channels and transporters are expected to become new therapeutic targets. In this review, ion channels and transporters associated with HCC are reviewed, and potential targets for new and effective therapies are proposed.
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Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.
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Carcinoma Hepatocelular , Proliferación Celular , Glucólisis , Neoplasias Hepáticas , Pantoprazol , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Glucólisis/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Ratones , Pantoprazol/farmacología , Masculino , Proliferación Celular/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Carcinogénesis/efectos de los fármacos , Dietilnitrosamina/toxicidad , Citocinas/metabolismo , Línea Celular Tumoral , Dieta Alta en Grasa/efectos adversosRESUMEN
Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a posttranslational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolismrelated genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, nonalcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.
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Ácido Láctico , Hepatopatías , Humanos , Ácido Láctico/metabolismo , Hepatopatías/metabolismo , Animales , Hígado/metabolismo , Hígado/patologíaRESUMEN
Solute carrier family 26 member 9 (SLC26A9) is a member of the Slc26a family of multifunctional anion transporters that functions as a Cl- channel in parietal cells during acid secretion. We explored the role of SLC26A9 in colorectal cancer (CRC) and its related mechanisms through clinical samples from CRC patients, CRC cell lines and mouse models. We observed that SLC26A9 was expressed at low levels in the cytoplasm of adjacent tissues, polyps and adenomas but was significantly increased in colorectal adenocarcinoma. Moreover, increased levels of SLC26A9 were associated with a high risk of disease and poor prognosis. In addition, downregulation of SLC26A9 in CRC cells induced cell cycle arrest and apoptosis but inhibited cell proliferation and xenograft tumor growth both in vitro and in vivo. Mechanistic analysis revealed that SLC26A9 was colocalized with ß-catenin in the nucleus of CRC cells. The translocation of these two proteins from the cytoplasm to the nucleus reflected the activation of Wnt/ß-catenin signaling, and promoted the transcription of downstream target proteins, including CyclinD1, c-Myc and Snail, but inhibited the expression of cytochrome C (Cyt-c), cleaved Caspase9, cleaved Caspase3 and apoptosis-inducing factor (AIF). CRC is accompanied by alteration of epithelial mesenchymal transition (EMT) markers. Meanwhile, further studies showed that in SW48 cells, overexpressing SLC26A9 was cocultured with the ß-catenin inhibitor XAV-939, ß-catenin was downregulated, and EMT was reversed. Our study demonstrated SLC26A9 may be responsible for alterations in the proliferative ability and aggressive potential of CRC by regulating the Wnt/ß-catenin signaling pathway.
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BACKGROUND: S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain. METHODS AND RESULTS: In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice. CONCLUSIONS: Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.
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Enfermedad del Hígado Graso no Alcohólico , Proteína A6 de Unión a Calcio de la Familia S100 , Animales , Humanos , Ratones , Apoptosis , Autofagia , Proteínas de Unión al Calcio/genética , Proteína A6 de Unión a Calcio de la Familia S100/metabolismoRESUMEN
Hepatocellular carcinoma is the most common type of liver cancer and associated with a high fatality rate. This disease poses a major threat to human health worldwide. A considerable number of genetic and epigenetic factors are involved in the development of hepatocellular carcinoma. However, the molecular mechanism underlying the progression of hepatocellular carcinoma remains unclear. Karyopherin subunit alpha 2 (KPNA2), also termed importin α1, is a member of the nuclear transporter family. In recent years, KPNA2 has been gradually linked to the nuclear transport pathway for a variety of tumor-associated proteins. Furthermore, it promotes tumor development by participating in various pathophysiological processes such as cell proliferation, apoptosis, immune response, and viral infection. In hepatocellular carcinoma, it has been found that KPNA2 expression is significantly higher in liver cancer tissues versus paracancerous tissues. Moreover, it has been identified as a marker of poor prognosis and early recurrence in patients with hepatocellular carcinoma. Nevertheless, the role of KPNA2 in the development of hepatocellular carcinoma remains to be determined. This review summarizes the current knowledge on the pathogenesis and role of KPNA2 in hepatocellular carcinoma, and provides new directions and strategies for the diagnosis, treatment, and prediction of prognosis of this disease.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Transporte Activo de Núcleo Celular , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carioferinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologíaRESUMEN
Besides causing severe acute respiratory syndrome (SARS), SARScoronavirus 2 (SARSCoV2) also harms the digestive system. Given the appearance of numerous cases of SARSCoV2, it has been demonstrated that SARSCoV2 is able to harm target organs such as the gastrointestinal tract, liver and pancreas, and either worsen the condition of patients with basic digestive illnesses or make their prognosis poor. According to several previously published studies, angiotensinconverting enzyme II (ACE2) and transmembrane serine protease II (TMPRSS2) are expressed either singly or in combination in the digestive system and in other regions of the human body. In order to change the viral conformation, create a fusion hole and release viral RNA into the host cell for replication and transcription, SARSCoV2 is capable of binding to these two proteins through the spike protein on its surface. As a result, the body experiences an immune reaction and an inflammatory reaction, which may lead to nausea, diarrhea, abdominal pain and even gastrointestinal bleeding, elevated levels of liver enzymes, acute liver injury, pancreatitis and other serious lesions. In order to provide possible strategies for the clinical diagnosis and treatment of digestive system diseases during the COVID19 pandemic, the molecular structure of SARSCoV2 and the mechanism via which SARSCoV2 enters the human body through ACE2 and TMPRSS2 were discussed in the present review, and the clinical manifestations of SARSCoV2 infection in the digestive system were also summarized. Finally, the expression characteristics of ACE2 and TMPRSS2 in the main target organs of the digestive system were described.
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COVID-19 , Enfermedades del Sistema Digestivo , Humanos , Enzima Convertidora de Angiotensina 2/genética , COVID-19/complicaciones , Pandemias , SARS-CoV-2 , Enfermedades del Sistema Digestivo/virologíaRESUMEN
Liver cancer is one of the most common cancers in the world, and the rate of liver cancer is high due to the of its illness. The main risk factor for liver cancer is infection with the hepatitis B virus (HBV), but a considerable number of genetic and epigenetic factors are also directly or indirectly involved in the underlying pathogenesis of liver cancer. In particular, the apolipoprotein B mRNA editing enzyme, catalytic peptide-like protein (APOBEC) family (DNA or mRNA editor family), which has been the focus of virology research for more than a decade, has been found to play a significant role in the occurrence and development of various cancers, providing a new direction for the research of liver cancer. APOBEC3B is a cytosine deaminase that controls a variety of biological processes, such as protein expression, innate immunity, and embryonic development, by participating in the process of cytidine deamination to uridine in DNA and RNA. In humans, APOBEC3B has long been known as a DNA editor for limiting viral replication and transcription. APOBEC3B is widely expressed at low levels in a variety of normal tissues and organs, but it is significantly upregulated in different types of tumor tissues and tumor lines. Thus, APOBEC3B has received increasing attention in various cancers, but the role of APOBEC3B in the occurrence and development of liver cancer due to infection with HBV remains unclear. This review provides a brief introduction to the pathogenesis of hepatocellular carcinoma induced by HBV, and it further explores the latest results of APOBEC3B research in the development of HBV and liver cancer, thereby providing new directions and strategies for the treatment and prevention of liver cancer.
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Integrins allow cells to adhere to the extracellular matrix and promote the recruitment of other integrins, resulting in the formation of focal adhesion sites at the binding sites. Focal adhesion sites play essential roles in the assembly of the cytoskeleton and are vital in shaping the structure of cells. They also play other regulatory roles by influencing numerous biological functions, such as cell proliferation and apoptosis. Hydrogen peroxideinducible clone 5 (Hic5) is a member of the Paxillin family of proteins and is an adhesive plaque scaffolding protein. Its expression can be detected in both vascular and smooth muscle cells. Thus, it plays an essential role in vascular remodeling, as well as in fibrotic diseases. Hic5 functions as a coactivator of steroid receptors, thus playing a role in steroid hormonedependent diseases. It also plays a vital role in the invasive metastasis of various types of cancer. Moreover, several studies have demonstrated that Hic5 plays a critical role in transcriptional regulation, as well as in numerous signaling pathways. Therefore, the inhibition of the functions of Hic5 may prevent the development or halt the progression of several diseases. Its use as a therapeutic target in future investigations may thus aid in the treatment of several diseases, including various types of cancer. The present review article focused on the expression and functions of Hic5 in different organs, with the aim of highlighting novel possibilities for future research.
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Peróxido de Hidrógeno , Integrinas , Adhesión Celular/fisiología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Hormonas , Peróxido de Hidrógeno/metabolismo , Integrinas/metabolismo , Paxillin/metabolismo , FosforilaciónRESUMEN
As a major protongated cation channel, acidsensitive ion channels (ASICs) can perceive large extracellular pH changes. ASICs play an important role in the occurrence and development of diseases of various organs and tissues including in the heart, brain, and gastrointestinal tract, as well as in tumor proliferation, invasion, and metastasis in acidosis and regulation of an acidic microenvironment. The permeability of ASICs to sodium and calcium ions is the basis of their physiological and pathological roles in the body. This review summarizes the physiological and pathological mechanisms of ASICs in digestive system diseases, which plays an important role in the early diagnosis, treatment, and prognosis of digestive system diseases related to ASIC expression.
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Canales Iónicos Sensibles al Ácido , Neuronas , Canales Iónicos Sensibles al Ácido/genética , Canales Iónicos Sensibles al Ácido/metabolismo , Ácidos , Sistema Digestivo/metabolismo , Concentración de Iones de Hidrógeno , Iones/metabolismo , Neuronas/metabolismo , Sodio/metabolismoRESUMEN
BACKGROUND: Solute carrier family 26 member (SLC26A9) is a Cl- uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9-/- mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients. METHODS: The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines. RESULTS: We found that both complete and parietal cell-selective Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl-/HCO3- exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion. CONCLUSIONS: Our data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous SLC26A9 expression in GC cells reduces their malignant behavior.
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Antiportadores , Lesiones Precancerosas , Neoplasias Gástricas , Transportadores de Sulfato , Animales , Antiportadores/genética , Antiportadores/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Inmunohistoquímica , Metaplasia/metabolismo , Metaplasia/patología , Ratones , Lesiones Precancerosas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismoRESUMEN
High-fat diet (HFD) is widely used in animal models of many diseases, it helps to understand the pathogenic mechanism of related diseases. Several dietary fats were commonly used in HFD, such as corn oil, peanut oil, soybean oil, sunflower oil, and lard. However, it was reported that different dietary fat could have completely different effects on physiological indicators and the gut microbiome, and the sources of dietary fat used in high-fat diet research have not been comprehensively compared. In this research, we conduct comparative experiments on various sources of dietary fats to test their different effects during the high-fat diet intervention. We investigated the effects of twelve common dietary fats in high-fat diet intervention of mice, body/liver weight changes, four blood lipid indices, and gut microbiome were analyzed. Our results showed that the source of dietary fat used in high-fat diet significantly affects the changes of body/liver weight and triglyceride (TRIG) in the blood. Furthermore, the intervention of canola oil increased the alpha diversity of gut microbiota, and lard has decreased diversity compared with the control group. The composition of saturated fatty acid (SFA) in fat has the most significant effects on the gut microbiome. All dietary fats treatments have an increasing Firmicutes abundance and a reduced Bacteroidetes abundance in gut microbiome, while the canola oil has a slight variation compared to other intervention groups, and the lard group has the largest changes. This study showed that different types of dietary fat have different effects on the body indicators and intestinal microbiota of mice, and canola oil produced less disturbance than other types of dietary fats in high-fat diet.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Animales , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/farmacología , Ratones , Aceite de Brassica napus , TriglicéridosRESUMEN
Liver disease is a significant health challenge worldwide and comprises liver fibrosis and cirrhosis, viral hepatitis, fatty liver, nonalcoholic fatty liver disease, alcoholic liver disease and hepatocellular carcinoma (HCC). Due to the lack of effective treatments, the prognosis of endstage liver disease (including advanced liver cirrhosis and HCC) is often poor. S100 proteins are a type of Ca2+ binding protein, which are expressed in a cellspecific manner in vertebrates. These proteins are involved in numerous functions, such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signals and regulation of extracellular factors that affect cellular activity by binding to a range of membrane receptors. Evidence has shown that S100 proteins serve key roles in the occurrence and development of liver disease and can be used as potential therapeutic targets or diagnosis markers. For example, certain studies have suggested that blocking S100 protein expression may be an innovative treatment strategy. The present review focuses on the functions of the S100 protein family in liver disease.
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Hepatopatías/metabolismo , Proteínas S100/metabolismo , Animales , Calcio/metabolismo , Manejo de la Enfermedad , Humanos , Hígado/metabolismo , Hígado/patología , Hepatopatías/patología , Hepatopatías/terapia , Proteínas S100/análisisRESUMEN
BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.
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Celecoxib/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Celecoxib/efectos adversos , Celecoxib/uso terapéutico , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Intestinal calcium absorption from the diet plays important role in maintaining calcium homeostasis in the body. Estrogen exerts wide physiological and pathological effects in the human. Previous studies have shown that estrogen is involved in the intestinal calcium absorption. In this study, we made investigation on the mechanism of estrogen action on duodenal calcium absorption. METHODS: The experiments were performed in mice, human, and human duodenal epithelial cells, SCBN cells. Murine duodenal calcium absorption was measured by using single pass perfusion of the duodenum in vivo. The calcium absorption of SCBN cells was evaluated by calcium imaging system. The expression of calcium transport proteins, transient receptor potential cation channel (TRPV6) and plasma membrane calcium pump (PMCA1b), in the duodenum or SCBN cells were analyzed by western blot. RESULTS: The duodenal calcium absorption in ovariectomized mice was significantly decreased, compared with control female mice, which returned to control level after 17ß-estradiol replacement treatment. Estrogen regulated the expressions of TRPV6 and PMCA1b in murine and human duodenal mucosae and SCBN cells. The further results from SCBN cells showed that 17ß-estradiol regulated calcium influx through the respective effects of estrogen receptor (ER) É and ß on TRPV6 and PMCA1b. CONCLUSION: Estrogen regulates duodenal calcium absorption through differential role of ERÉ and ERß on duodenal epithelial cellular TRPV6 and PMCA1b. The study further elucidates the mechanism of estrogen on the regulation of intestinal calcium absorption.
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Canales de Calcio/metabolismo , Calcio/metabolismo , Duodeno/fisiología , Estradiol/farmacocinética , Mucosa Intestinal/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Receptores de Estrógenos/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/fisiología , Células Cultivadas , Estrógenos/farmacocinética , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , RatonesRESUMEN
After the publication of the article, the authors informed us that they had consent from the patients involved in the study, but not from the nextofkin of the patients, for their clinical data to have been published (Fig. 1AE). Following on from a request made by the Ethics Committee of the Affiliated Hospital of Zunyi Medical College that these data either be replaced in the article, or that the article be retracted, the authors identified 10 new volunteers and asked the patients and their families to sign informed consent according to ethical requirements. The experiments were repeated according to the previous experimental design, and novel data were obtained. The results obtained were consistent with the previous clinical data.The revised version of Fig. 1, including the data from the new patients, is shown opposite. As stated, the revised data shown for Fig. 1AE do not affect the overall conclusions reported in the paper. The authors apologize to the Editor of Oncology Reports and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 37: 14511460, 2017; DOI: 10.3892/or.2017.5386].
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BACKGROUND: The pathogenesis of Helicobacter pylori (H. pylori) infection-induced duodenal ulcer remains to be elucidated. Duodenal mucosal bicarbonate secretion is the most important protective factor against acid-induced mucosal injury. We previously revealed that H. pylori infection downregulated the expression and functional activity of duodenal mucosal cystic fibrosis transmembrane conductance regulator (CFTR) and solute linked carrier 26 gene family A6 (SLC26A6) which are the two key duodenal mucosal epithelial cellular bicarbonate transporters to mediate duodenal bicarbonate secretion. In this study, we investigated the mechanism of H. pylori infection-induced duodenal CFTR and SLC26A6 expression downregulation. RESULTS: We found that H. pylori infection induced the increase of serum transforming growth factor ß (TGFß) level and duodenal mucosal TGFß expression and the decrease of duodenal mucosal CFTR and SLC26A6 expressions in C57 BL/6 mice. The results from the experiments of human duodenal epithelial cells (SCBN) showed that H. pylori increased TGFß production and decreased CFTR and SLC26A6 expressions in SCBN cells. TGFß inhibitor SB431542 reversed the H. pylori-induced CFTR and SLC26A6 expression decreases. The further results showed that TGFß directly decreased CFTR and SLC26A6 expressions in SCBN cells. TGFß induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and P38 MAPK inhibitor SB203580 reversed the TGFß-induced CFTR and SLC26A6 expression decreases. CONCLUSIONS: H. pylori infection downregulates duodenal epithelial cellular CFTR and SLC26A6 expressions through TGFß-mediated P38 MAPK signaling pathway, which contributes to further elucidating the pathogenesis of H. pylori-associated duodenal ulcer.
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Antiportadores/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Regulación hacia Abajo , Duodeno/metabolismo , Infecciones por Helicobacter , Helicobacter pylori/patogenicidad , Transportadores de Sulfato/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antiportadores/genética , Bicarbonatos/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Duodeno/microbiología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Infecciones por Helicobacter/microbiología , Imidazoles/antagonistas & inhibidores , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Piridinas/antagonistas & inhibidores , Transportadores de Sulfato/genética , Factor de Crecimiento Transformador beta/genética , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
TGFß plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFß in human HCC. In HepG2 and Huh7 cells, TGFß-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFß on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFß upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFß signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.Significance: TGFß induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFß on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564-76. ©2018 AACR.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Intercambiador de Sodio-Calcio/metabolismo , Canal Catiónico TRPC6/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Complejos Multiproteicos/metabolismo , Invasividad Neoplásica/patología , Trasplante de Neoplasias , Transducción de Señal/fisiología , Trasplante HeterólogoRESUMEN
BACKGROUND AND PURPOSE: Although Ca2+ signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca2+-mediated biological action. KEY RESULTS: Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca2+-free serosal solution and by several selective store-operated Ca2+ channels(SOC) blockers added to the serosal side of duodenal tissues. Furthermore, we found that CRAC/Orai channels may represent the molecular candidate of SOC in intestinal epithelium. CCh increased intracellular Ca2+ but not cAMP, and Ca2+ signaling mediated duodenal Cl- and HCO3- secretion in wild type mice but not in CFTR knockout mice. CCh induced duodenal ion secretion and stimulated PI3K/Akt activity in duodenal epithelium, all of which were inhibited by selective PI3K inhibitors with different structures. CCh-induced Ca2+ signaling also stimulated the phosphorylation of CFTR proteins and their trafficking to the plasma membrane of duodenal epithelial cells, which were inhibited again by selective PI3K inhibitors. MATERIALS AND METHODS: Functional, biochemical and morphological experiments were performed to examine ion secretion, PI3K/Akt and CFTR activity of mouse duodenal epithelium. Ca2+ imaging was performed on HT-29 cells. CONCLUSIONS AND IMPLICATIONS: Ca2+ signaling plays a critical role in intestinal ion secretion via CRAC/Orai-mediated SOCE mechanism on the serosal side of epithelium. We also demonstrated the molecular mechanisms of Ca2+ signaling in CFTR-mediated secretion via novel PI3K/Akt pathway. Our findings suggest new perspectives for drug targets to protect the upper GI tract and control liquid homeostasis in the small intestine.
RESUMEN
Na+/H+ exchanger isoform 1 (NHE1) is known to play a key role in regulating intracellular pH and osmotic homeostasis and is involved in the development and progression of several types of cancer. However, the function and specific mechanism of NHE1 in gastric cancer (GC) are not clearly understood. In the present study, we report that NHE1 is overexpressed in tissues and cell lines from GC patients, and knockdown or inhibition of NHE1 suppressed GC cell proliferation via regulation of G1/S and G2/M cell cycle phase transitions, concomitant with a marked decrease in positive cell cycle regulators, including cyclin D1 and cyclin B1. Likewise, NHE1 was required for GC cell migration and invasion through the regulation of epithelial-mesenchymal transition (EMT) proteins, and NHE1 inhibition resulted in an acidic intracellular environment, providing possible mechanisms underlying NHE1-mediated GC progression both in vitro and in vivo. These data highlight the important role of NHE1 in GC progression and suggest that NHE1 may be a useful target for GC therapy.