Impact of Helicobacter pylori colonization density and depth on gastritis severity.

BACKGROUND AND OBJECTIVES: Helicobacter pylori (H. pylori) infection is the most common etiology of chronic gastric. H. pylori gastritis would gradually evolve into gastric atrophy, intestinal metaplasia, dysplasia and malignant lesions. Herein, this study aimed to investigate the potential impact of H. pylori colonization density and depth on the severity of histological parameters of gastritis. METHODS: A prospective monocentric study was conducted from December 2019 to July 2022, enrolling patients with confirmed chronic H. pylori infection via histopathological evaluation. H. pylori colonization status was detected by immunohistochemical staining, pathological changes of gastric specimens were detected by hematoxylin eosin staining. Epidemiological, endoscopic and histopathological data were collected. RESULTS: A total of 1120 patients with a mean age of 45.8 years were included. Regardless of the previous history of H. pylori eradication treatment, significant correlations were observed between the density and depth of H. pylori colonization and the intensity of gastritis activity (all P < 0.05). Patients with the lowest level of H. pylori colonization density and depth exhibited the highest level of mild activity. In whole participants and anti-H. pylori treatment-naive participants, H. pylori colonization density and depth were markedly correlated with the severity of chronic gastritis and gastric atrophy (all P < 0.05). H. pylori colonization density (P = 0.001) and depth (P = 0.047) were significantly associated with ulcer formation in patients naive to any anti-H. pylori treatment. No significant associations were observed between the density and depth of H. pylori colonization and other histopathological findings including lymphadenia, lymphoid follicle formation and dysplasia. CONCLUSIONS: As the density and depth of H. pylori colonization increased, so did the activity and severity of gastritis, along with an elevated risk of ulcer formation.

AMPK inhibits Smad3-mediated autoinduction of TGF-ß1 in gastric cancer cells.

We have previously shown that adenine monophosphate-activated protein kinase (AMPK) regulates transforming growth factor ß (TGF-ß)-triggered Smad3 phosphorylation. Here we report that AMPK inhibits TGF-ß1 production. First, metformin reduced mRNA levels of TGF-ß1 in gastric cancer cells, in parallel to the decrease of its protein abundance. The effects were more prominent in the cells containing LKB1, an upstream kinase of AMPK. Second, knockdown of Smad3 by siRNA abrogated the expression of TGF-ß1. Third, metformin suppressed firefly luciferase activity whose transcription was driven by TGF-ß1 promoter. In accordance, deletion of the putative binding site of Smad3 in the TGF-ß1 promoter region severely impaired the promoter activity and response to metformin. Fourth, in support of our in vitro study, clinical treatment of type 2 diabetes with metformin significantly reduced the plasma level of TGF-ß1. Finally, immunohistochemical studies revealed that TGF-ß1 was highly expressed in human gastric cancer tissues as compared with adjacent normal tissues. In contrast, p-AMPK exhibited opposite changes. Furthermore, the survival rate of gastric cancer patients was positively correlated with p-AMPK and negative with TGF-ß1. Therefore, our present studies depict a mechanism underlying AMPK suppression of TGF-ß1 autoinduction, which is mediated through inhibition of Smad3 phosphorylation and activation. Collectively, our study sheds a light on the potential usage of AMPK activators in the treatment of TGF-ß1-mediated gastric cancer progression.

Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling.

AMP-activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma-induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3-E1 cells, concurrent with up-regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma-induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up-regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.

AMP-activated protein kinase regulates cancer cell growth and metabolism via nuclear and mitochondria events.

Adenine monophosphate-activated protein kinase (AMPK) is a fuel sensing enzyme that is activated in shortage of energy and inhibited in its surplus. Cancer is a metabolic disease characteristic of aerobic glycolysis, namely Warburg effect, and possesses heterogeneity featured by spatiotemporal hypoxia and normoxia, where AMPK is deeply implicated. The present study delineates the regulation of mitochondrial functions by AMPK in cancer cells. On the one hand, AMPKα subunit binds to mitochondria independently of ß subunit and targeting AMPK to mitochondria facilitates oxidative phosphorylation and fatty acid oxidation, and inhibits glycolysis. As such, mitochondrial AMPK inhibits the growth of cancer cells and tumorigenesis. On the other hand, ablation of the ß subunits completely abolishes AMPK activity and simultaneously leads to decreases in mitochondria DNA and protein contents. The effect of the ß deletion is rescued by overexpression of the active mutant of bulky AMPKα1 subunit. In conjunction, the transcriptional factors PGC1α and Nrf-1 are up-regulated by LKB1/AMPK, an event that is abolished in the absence of the ß subunits. Intriguingly, the stimulation of mitochondria biogenesis is not achieved by mitochondria-targeted AMPK. Therefore, our study suggests that AMPK inhibits cancer cell growth and tumorigenesis via regulation of mitochondria-mediated metabolism.

Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism.

AMP-activated protein kinase (AMPK) is a conserved sensor of cellular energy change and is activated by increased AMP/ATP and/or ADP/ATP ratios. AMPK maintains the energy balance by decreasing the ATP-consuming processes such as transcription of synthetic fat genes and rRNA, the translation of ribosomal proteins, synthesis of cholesterol and fatty acid, while the metabolic pathways such as glucose and fatty transport, fatty acid oxidation, autophagy, mitochondrial synthesis and oxidative metabolism are increased to preserve ATP during energy deficiency. Recent advance has demonstrated that AMPK activity has a close association with the initiation and progression in various cancers. Here we review the mechanisms that AMPK controls energy metabolism through regulating ATP synthesis and consumption, and further discuss the deregulation of AMPK in cancers.

Down-regulation of adenosine monophosphate-activated protein kinase activity: A driver of cancer.

Adenosine monophosphate-activated protein kinase (AMPK), a serine/threonine protein kinase, is known as "intracellular energy sensor and regulator." AMPK regulates multiple cellular processes including protein and lipid synthesis, cell proliferation, invasion, migration, and apoptosis. Moreover, AMPK plays a key role in the regulation of "Warburg effect" in cancer cells. AMPK activity is down-regulated in most tumor tissues compared with the corresponding adjacent paracancerous or normal tissues, indicating that the decline in AMPK activity is closely associated with the development and progression of cancer. Therefore, understanding the mechanism of AMPK deactivation during cancer progression is of pivotal importance as it may identify AMPK as a valid therapeutic target for cancer treatment. Here, we review the mechanisms by which AMPK is down-regulated in cancer.

LKB1/AMPK inhibits TGF-ß1 production and the TGF-ß signaling pathway in breast cancer cells.

Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that maintains energy homeostasis in both normal and cancerous cells, and has emerged as a tumor suppressor. The present study aims to delineate the functional relationship between AMPK and transforming growth factor beta (TGF-ß). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-ß-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPKα1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-ß. Furthermore, AMPK activation reduced the promoter activity of TGF-ß1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-ß1, as compared with those without metformin. A significant reduction of serum TGF-ß1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-ß1, leading to reduction of its concentration in serum. Finally, metformin suppressed epithelial-to-mesenchymal transition of mammary epithelial cells. Taken together, our study demonstrates that AMPK exerts multiple actions on TGF-ß signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.

AMPK Inhibits the Stimulatory Effects of TGF-ß on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition.

AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelial-to-mesenchymal transition (EMT) by regulating the canonical transforming growth factor ß (TGF-ß) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-ß-induced Smad2/3 phosphorylation in cancer cells in a dose-dependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKα1 subunit, whereas the expression of a dominant negative mutant of AMPKα1 or ablation of AMPKα subunits greatly enhanced TGF-ß stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-ß-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-ß-stimulated cancer cell migration. Finally, TGF-ß induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.

SMAD7: a timer of tumor progression targeting TGF-ß signaling.

In the context of cancer, transforming growth factor ß (TGF-ß) is a cell growth suppressor; however, it is also a critical inducer of invasion and metastasis. SMAD is the important mediator of TGF-ß signaling pathway, which includes receptor-regulated SMADs (R-SMADs), common-mediator SMADs (co-SMADs), and inhibitory SMADs (I-SMADs). I-SMADs block the activation of R-SMADs and co-SMADs and thus play important roles especially in the SMAD-dependent signaling. SMAD7 belongs to the I-SMADs. As an inhibitor of TGF-ß signaling, SMAD7 is overexpressed in numerous cancer types and its abundance is positively correlated to the malignancy. Emerging evidence has revealed the switch-in-role of SMAD7 in cancer, from a TGF-ß inhibiting protein at the early stages that facilitates proliferation to an enhancer of invasion at the late stages. This role change may be accompanied or elicited by the tumor microenvironment and/or somatic mutation. Hence, current knowledge suggests a tumor-favorable timer nature of SMAD7 in cancer progression. In this review, we summarized the advances and recent findings of SMAD7 and TGF-ß signaling in cancer, followed by specific discussion on the possible factors that account for the functional changes of SMAD7.

Prognostic significance and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer: A clinicopathological study.

BACKGROUND: The TGF-ß/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis. SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer. AIM: To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer. METHODS: This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years (median age 65) between July 2006 and April 2007. Patients were followed up until death or the study ended (median follow-up duration of 28.5 mo). The samples were used to generate tissue microarrays (TMAs) for immunohistochemical (IHC) staining. The expressions of TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 in gastric cancer (GC) tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients. Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015. The relationship between TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient. The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test. A survival curve was generated using the Kaplan-Meier survival analysis. RESULTS: TGFß-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent non-cancerous tissue. The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site [pSMAD3C(S423/425): 51.0% and pSMAD3L(S204): 31.6%]. High expression of pSMAD3L(S204) was significantly correlated with larger tumors (P = 0.038) and later N stages (P = 0.035). Additionally, high expression of VEGFR-1 was closely correlated with tumor size (P = 0.015) and pathological grading (P = 0.013). High expression of both pSMAD3L(S204) and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival (OS). Multivariate analysis indicated that high expression of pSMAD3L(S204) and VEGFR-1 were independent risk factors for prognosis in GC patients. VEGFR-1 protein expression was correlated with TGF-ß1 (r = 0.220, P = 0.029), pSMAD3C(S423/425) (r = 0.302, P = 0.002), and pSMAD3L(S204) (r = 0.201, P = 0.047), respectively. Simultaneous overexpression of pSMAD3L(S204) and VEGFR-1 was associated with poor OS in gastric cancer patients. CONCLUSION: Co-upregulation of pSMAD3L(S204) and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis, and pSMAD3L(204) may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

Single-primer-limited amplification: a method to generate random single-stranded DNA sub-library for aptamer selection.

The amplification of a random single-stranded DNA (ssDNA) library by polymerase chain reaction (PCR) is a key step in each round of aptamer selection by systematic evolution of ligands by exponential enrichment (SELEX), but it can be impeded by the amplification of by-products due to the severely nonspecific hybridizations among various sequences in the PCR system. To amplify a random ssDNA library free from by-products, we developed a novel method termed single-primer-limited amplification (SPLA), which was initiated from the amplification of minus-stranded DNA (msDNA) of an ssDNA library with reverse primer limited to 5-fold molar quantity of the template, followed by the amplification of plus-stranded DNA (psDNA) of the msDNA with forward primer limited to 10-fold molar quantity of the template and recovery of psDNA by gel excision. We found that the amount of by-products increased with the increase of template amount and thermal cycle number. With the optimized template amount and thermal cycle, SPLA could amplify target ssDNA without detectable by-products and nonspecific products and could produce psDNA 16.1 times as much as that by asymmetric PCR. In conclusion, SPLA is a simple and feasible method to efficiently generate a random ssDNA sub-library for aptamer selection.

Application of electrogastrogram in assessment of gastric motility in acute pancreatitis.

Background: Electrogastrogram (EGG) can reflect gastric motility disorders in many diseases, but its application in acute pancreatitis (AP) has not been studied. Therefore, our study aimed to investigate the value of EGG in assessing the existence of gastric motility disorder in patients with AP and in predicting the severity of AP. Methods: Patients with AP admitted to the First Affiliated Hospital of Nanchang University from June 2020 to December 2020 were enrolled. Five EGG parameters (Percentage of normal gastric slow wave (PNGSW), main frequency, average frequency, percentage of gastric tachycardia (PGT), percentage of gastric bradycardia (PGB)) were collected. The receiver operating characteristic (ROC) curve was constructed to judge the predictive value of EGG parameters to AP severity. Results: The PNGSW in AP patients was significantly lower than that of the control group (p < 0.05), and the PGB was higher in AP patients than that of the control group (p < 0.05). The area under curve (AUC) of the PNGSW and the PGB in diagnosing non-mild acute pancreatitis (N-MAP) were 0.777 (95% CI: 0.676-0.877, p < 0.001) and 0.775 (95% CI: 0.670-0.879, p < 0.001) respectively. After combining with C-reactive protein, the accuracy, sensitivity and specificity of predicting N-MAP were improved. Conclusion: EGG parameters can well reflect the gastric motility disorder of AP patients. The PNGSW and the PGB can be used to predict the occurrence of N-MAP.

Early evaluation of waist-to-height ratio for the prediction of worsening acute pancreatitis.

The purpose of this study was to evaluate the association between the waist-to-height ratio (WHtR) and the aggravation of acute pancreatitis (AP). This prospective study included AP patients treated from May 2019 to December 2019 in the Department of Gastroenterology, the First Affiliated Hospital of Nanchang University. Receiver operating characteristic curves were constructed to determine the optimal threshold values for predicting the aggravation of AP. Risk factor analysis was performed via logistic regression analysis. Of 258 patients included in this study, 77 (29.84%) were diagnosed with mild acute pancreatitis, 120 (46.51%) with moderately severe acute pancreatitis, and 61 (23.64%) with severe acute pancreatitis (SAP). WHtR, waist circumference, weight, and body mass index were all associated with AP severity, and the highest area under the receiver operating characteristic value was observed for WHtR. The optimal threshold WHtR value for predicting SAP was 0.567. Multivariate logistic regression analysis identified WHtR ≥ 0.567 as independent risk factor for SAP. Moreover, the hospital stay was longer and intensive care unit admission rate was higher among AP patients with a WHtR ≥ 0.567. The WHtR was found to be closely related to the severity of AP and an independent risk factor for the aggravation of AP. This simple parameter can aid the early prediction of AP progression, thereby facilitating early intervention and improving patient outcomes.

Roles of salt­inducible kinases in cancer (Review).

Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP­activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.

RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer.

Background: Lung cancer is a highly malignant disease, primarily due to its propensity for metastasis. AMP-activated protein kinase (AMPK), the principal downstream effector of Liver Kinase B1 (LKB1), orchestrates a broad spectrum of molecular targets, thereby constraining tumor invasion and metastasis. In parallel, the RNA-binding protein RBMS3 (RNA-binding motif, single-stranded-interacting protein 3) plays a pivotal role in the epithelial-mesenchymal transition (EMT), a pivotal process in tumorigenesis. Therefore, our research aims to clarify the important role of RBMS3 as a mediator in the LKB1/AMPK inhibition of tumor invasion and metastasis. Methods: We investigated the expression and correlation between RBMS3 and LKB1 in lung cancer tissues utilizing immunohistochemistry and TCGA-LUAD data, respectively. The relationship between RBMS3 and clinical pathological features and prognosis of lung cancer was also analyzed. The functions of RBMS3 in lung cancer cell proliferation, invasion, and migration were investigated in real-time in vitro. Additionally, we investigated the effects of AMPK agonists and inhibitors to explore the mediating role of RBMS3 in AMPK-induced inhibition of lung cancer invasion and migration. Results: The IHC and TCGA data both revealed low expression of RBMS3 in lung cancer. Moreover, we found that low expression of RBMS3 was positively associated with lung cancer's histological grade, clinical stage, and N stage. Additionally, low RBMS3 expression was associated with poor overall survival. Cox regression analysis revealed that RBMS3 was an independent prognostic factor for lung cancer patients. In vitro experiments verified that RBMS3 inhibited lung cancer cell proliferation, invasion, and migration. Furthermore, our findings suggested that RBMS3 played an essential role in mediating AMPK's inhibitory effect on lung cancer invasion and migration. Conclusion: Our study highlights a novel mechanism by which LKB1/AMPK pathway activation inhibits lung cancer invasion and metastasis by promoting RBMS3 expression, offering insights in developing innovative lung cancer therapies.

AMP-activated protein kinase re-sensitizes A549 to paclitaxel via up-regulating solute carrier organic anion transporter family member 1B3 expression.

Paclitaxel (PTX) is a common antineoplastic drug whose functionality is often restricted by drug resistance. Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a PTX influx transporter and its low expression has been proved to be relevant with PTX resistance. It has been widely reported that AMP-activated protein kinase (AMPK) could re-sensitize tumor cells to PTX. Our gene array result demonstrates AMPK up-regulated SLCO1B3. In this paper, we have tried to explain the relationships between PTX, SLCO1B3 and AMPK. First, we have verified the proliferative inhibition of PTX on A549 and found that PTX could inhibit A549 cells proliferation. Then, we have explored the relationship between SLCO1B3 and PTX: SLCO1B3 expression significantly decreased when A549 cells were treated with PTX or in A549 PTX resistant cells (A549-PTX) and the intracellular PTX concentration in A549-PTX was also lower. When treated with metformin/LKB1, both SLCO1B3 expression and intracellular PTX concentration have increased. Knockdown of AMPK has induced decreased SLCO1B3 expression. Moreover, in vitro and in vivo experiments have showed that metformin not only obviously inhibited A549-PTX tumor xenograft and A549-PTX proliferation alone, but also enhanced PTX efficacy to A549-PTX and this may be relevant to SLCO1B3. To verify it, we have treated A549 cells with AMPK both activators and an inhibitor, and then found that AMPK activators could weaken the PTX effect in inhibiting SLCO1B3 while its inhibitor has opposite effect. With knockdown of SLCO1B3, the effect of AMPK in re-sensitizing A549 to paclitaxel has decreased. To sum up, activation of AMPK can up-regulate SLCO1B3 expression, enhance the sensitivity of A549 cells to PTX, providing a new way to re-sensitize PTX resistance.

Ferroptosis in hepatic ischemia­reperfusion injury: Regulatory mechanisms and new methods for therapy (Review).

Ischemia­reperfusion injury (IRI), also called reoxygenation injury, is the outcome of inflammatory processes and oxidative damage through the induction of oxidative stress. In the clinical setting, IRI contributes to severe hepatic injury, including liver cell death by apoptosis and ferroptosis. Ferroptosis is a novel type of cell death in hepatic IRI that involves small molecules that inhibit glutathione biosynthesis or glutathione peroxidase 4 (GPX4), which is a glutathione­dependent antioxidant enzyme, causing mitochondrial damage. Currently, ferroptosis has been systematically described in neurological settings, kidney diseases and different types of cancer, while few studies have analysed the presence of ferroptosis and the regulatory mechanism of ferroptosis in hepatic IRI. Exploring the exact role played by ferroptosis in the liver following hepatic IRI in accordance with existing evidence and mechanisms could guide potential therapeutic interventions and provide a novel research avenue.

Regulation of gene transcription of B lymphoma Mo-MLV insertion region 1 homolog (Review).

B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is a core protein component of the polycomb repressive complex 1 that inhibits cell senescence and maintains the self-renewal ability of stem cells via downregulation of p16Ink4a and p19Arf expression. Bmi-1 serves an important role in hematopoietic stem cell maintenance and neurodevelopment during embryonic development, and it has been shown to enhance tumorigenesis by promoting cancer stem cell self-renewal and epithelial to mesenchymal transition. Emerging evidence suggests that Bmi-1 overexpression is closely related to the development and progression of various types of cancer, and that downregulation of Bmi-1 expression can inhibit the proliferation, invasion and metastasis of cancer cells. It is therefore important to elucidate the mechanisms underlying the regulation of Bmi-1 expression both under normal growth conditions and in malignant tissues. In the present review, the current body of knowledge pertaining to the transcriptional and post-transcriptional regulation of the BMI-1 gene is discussed, and the potential mechanisms by which Bmi-1 is dysregulated in various types of cancer are highlighted. Bmi-1 expression is primarily controlled via transcriptional regulation, and is regulated by the transcription https://www.ushuaia.pl/hyphen/?ln=en factors of the Myc family, including Myb, Twist1, SALL4 and E2F-1. Post-transcriptionally, regulation of Bmi-1 expression is inhibited by several microRNAs and certain small-molecule drugs. Thus, regulatory transcriptional factors are potential therapeutic targets to reduce Bmi-1 expression in cancer cells. Thus, the present review provides an up-to-date review on the regulation of BMI-1 gene expression at the transcriptional and post-transcriptional level.

Aryl hydrocarbon receptor nuclear translocator promotes the proliferation and invasion of clear cell renal cell carcinoma cells potentially by affecting the glycolytic pathway.

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that has been reported to play a vital role in regulating glycolysis, angiogenesis and apoptosis. Recently, ARNT has been reported to a play role in pancreatic-islet function in type 2 diabetes. However, the role of ARNT in kidney cancer has not yet been investigated. In the present study, ARNT expression was detected in tissues from patients with renal cell carcinoma (RCC) and in RCC cell lines. Oncomine, The Cancer Genome Atlas and cBioPortal were used to investigate the roles of ARNT in RCC. Cell migration and invasion assays were used to explore the molecular mechanisms involved. It was found that ARNT protein expression was elevated both in tissues from patients with clear cell RCC (ccRCC) and in different RCC cell lines. ARNT disruption using siRNA knockdown inhibited the migratory abilities and cell proliferation, potentially by altering the glycolysis pathway in vitro, as evidenced by decreased M2 type acetone kinase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 and hexokinase 2 expression. Taken together, the findings in the present study revealed a novel function of ARNT in ccRCC and indicated that ARNT promotes the proliferation and invasion of ccRCC, possibly through changes to the glycolytic pathway.

Inonotus obliquus polysaccharides induces apoptosis of lung cancer cells and alters energy metabolism via the LKB1/AMPK axis.

The present study explores the mechanisms underlying the anti-cancer action of Inonotus obliquus polysaccharides (IOP). Thus, we characterized the IOP components extracted from Chaga sclerotium and, found that the extracts contained 70% polysaccharides with an average molecular weight of 4.5 × 104 Da consisting of 75% glucose. We then showed that IOP extract activated AMPK in lung cancer cells expressing LKB1, suppressed cell viability, colony-formation, and triggered cell apoptosis. In conjunction, IOP downregulated Bcl-2, upregulated Bax, and enhanced cleavage of Caspase-3 and PARP. All of these effects were prevented by treatment with Compound C, a chemical inhibitor of AMPK. IOP diminished mitochondrial membrane potential (MMP), concurrent with decreases in oxidative phosphorylation and glycolysis, which was dependent on LKB1/AMPK. Finally, IOP at a dosage of 50 mg/kg significantly inhibited allograft tumor growth of the LLC1 cells in association with increased apoptosis. Collectively, our results demonstrate that IOP acts on cancer cells through a mechanism by which AMPK triggers the apoptotic pathway via the opening of mitochondrial permeability transition pore, and reducing MMP, leading to an inhibition of ATP production. Therefore, our study provides a solid foundation for the use of IOP as a promising alternative or supplementary medicine for cancer therapy.