👤 Liquan Cao

A hypoxia microenvironment plays a role in the initiation and progression of many cancer types, but its involvement in lung adenocarcinoma is still unclear. This study aimed to explore the potential correlation between hypoxia and lung adenocarcinoma and establish the hypoxia-associated gene signature in lung adenocarcinoma. Lung adenocarcinoma cases were retrieved from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The genes to be included in the hypoxia-associated signature were selected by performing univariate Cox regression analysis and lasso regression analysis. Then, the gene signature was verified by performing a survival analysis and constructing the multiple receiver operating characteristic (ROC) curve. The CIBERSORT tool was then used to investigate the potential correlation between the gene signature and immune cells. Moreover, a nomogram was constructed and evaluated by calculating the C-index. Four genes ( The hypoxia-associated gene signature established and validated in this study could be used as a potential prognostic factor in lung adenocarcinoma and may guide the immunotherapy choice. Show less

Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1; Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely Show less

Porphyromonas gingivalis (Pg) is one of the pathogenic bacteria that cause periodontal diseases, lipopolysaccharide (LPS) is the key factor that triggers alveolar bone absorption. This study explored the action of Axin 1 on Pg-LPS-induced osteoblasts injury, so as to search a possible treatment for periodontal diseases. Rat osteoblasts were dealt with Pg-LPS and Axin 1 knockdown alone or in combination. The effect of Pg-LPS and Axin 1 on osteoblast viability and apoptosis were detected by Cell Counting Kit-8 and flow cytometry. The expressions of alkaline phosphatase (ALP) and Axin 1 in processed osteoblasts were measured by western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. Furthermore, the role of Axin 1 knockdown in the levels of inflammatory cytokines and apoptosis-related proteins were also determined. Pg-LPS inhibited the viability of osteoblasts and promote apoptosis with concentration and time dependence. ALP expression in Pg-LPS-treated osteoblasts was reduced, while Axin 1 expression was increased. On the one hand, Axin 1 knockdown reversed the Pg-LPS-induced reduction of cell activity and pro-apoptosis effect. On the other hand, Axin 1 knockdown not only improved the ALP activity of Pg-LPS-treated cells, but also reduced the elevation of inflammatory cytokines (TNF-α, IL-1β and IL-6) caused by Pg-LPS. Moreover, Pg-LPS increased the expressions of cleaved Caspase-3 and Bax, and inhibited Bcl-2 expressed, which was rescued by Axin 1 knockdown. Axin 1 knockdown inhibited Pg-LPS-induced osteoblastic apoptosis by regulating the levels of inflammatory cytokines, which may be helpful for the treatment of periodontal diseases. Show less

Macrophages differentiated into a classically activated (M1) or alternatively activated phenotype (M2) in infection and tumor, but the precise effects of glycolysis and oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on macrophage polarizations were investigated using a pharmacological approach in mice. 2-Deoxy-D-glucose (2-DG) treatments, which blocks the key enzyme hexokinase of glycolysis, efficiently inhibits a specific switch to M1 lineage, decreasing the secretion of pro-inflammatory cytokines and expressions of co-stimulatory molecules associated with relieving infectious inflammation Show less

Metabolic abnormality is the major feature of laryngeal squamous cell carcinoma (LSCC), however, the underlying mechanism remain largely elusive. Fatty acid desaturase 1 (FADS1), as the key rate-limiting enzyme of polyunsaturated fatty acids (PUFAs), catalyzes dihomo-gamma-linolenic acid (DGLA) to arachidonic acid (AA). In this study, we reported that the expression of FADS1 was upregulated in LSCC, high FADS1 expression was closely associated with the advanced clinical features and poor prognosis of the recurrent LSCC patients after chemotherapy. Liquid chromatograph-mass spectrometry (LC-MS) analysis revealed that FADS1 overexpression induced greater conversion of DGLA to AA, suggesting an increased activity of FADS1. Similarly, the level of prostaglandin E2 (PGE Show less

Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. Huang-Qi San (HQS) is composed of three traditional Chinese medicines (Astragali Radix, Pueraria Radix and Cortex Mori Radicis) with a weight ratio of 1:2:1. HQS has been reported to be effective in improving glucose-lipid metabolism, but its underlying mechanism on NAFLD has not been fully understood. The purpose of the present study was to assess the protective effects of HQS on obesity-induced hepatic steatosis in rats fed with high fat diet (HFD). Our data revealed that administration of HQS (1.2 and 2.4 g/kg body weight) resulted in significant reduction in body weight (BW) and organs coefficients of visceral fat. The full-Body CT scan demonstrated that HQS reduced liver fat ratio, visceral and subcutaneous fat mass in a dose-dependent manner. Additionally, HQS decreased plasma TC, TG, FFA and FABP4 levels, normalized glucose and insulin levels, and improved the glucose tolerance. Pathological examination showed that HQS alleviated hepatic steatosis and reduced the cell size of epididymal visceral adipose tissue. Hepatic lipid accumulation was also reduced by HQS treatment compared with HFD fed rats. RNA-Seq analysis combining with qPCR demonstrated that the mRNA expression of some important glucose and lipid metabolism-related genes including Acat2, Apoc4, Bhmt, Cyp3a62, Cyp51, Egln3 (Phd3), Fads1, Fads2, Gnmt, Hmgcs1 and Pemt, were significantly changed by HQS treatment. Taken together, these results suggested that HQS had beneficial effects on glucose-lipid metabolism and hepatic steatosis, and its mechanism might be related to the functions of the genes in regulating glucose and lipid metabolism. Show less

Starch is an important substance that supplies energy to ruminants. To provide sufficient energy for high-yielding dairy ruminants, they are typically fed starch-enriched diets. However, starch-enriched diets have been proven to increase the risk of milk fat depression (MFD) in dairy cows. The starch present in ruminant diets could be divided into rumen-degradable starch (RDS) and rumen escaped starch (RES) according to their different degradation sites (rumen or intestine). Goats and cows have different sensitivities to MFD. Data regarding the potential roles of RDS in milk fat synthesis in the mammary tissue of dairy goats and in regulating the occurrence of MFD are limited. Eighteen Guanzhong dairy goats (day in milk = 185 ± 12 d) with similar parity, weight, and milk yield were selected and randomly assigned to one of three groups ( HRDS-induced goat MFD resulted from the downregulation of genes involved in lipogenesis, particularly, Show less

Invasive pulmonary aspergillosis is a life-threatening disease, particularly in immunocompromised patients, despite currently available therapy. IL-27 is an important regulatory cytokine in infection and immunity. However, its role in the pathogenesis of invasive pulmonary aspergillosis remains unknown. Here we found that Show less

The aim of this study was to investigate potential genetic overlap between essential tremor and Parkinson's disease in a cohort of 825 subjects from an Eastern Chinese population. A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect three essential tremor-related single nucleotide polymorphisms. Odds ratio (OR) and 95% confidential interval (CI) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. Our results demonstrated that the odds ratios of rs3794087 of SLC1A2, rs9652490 of LINGO1, and rs17590046 of PPARGC1A were 0.71 (95% CI = 0.55-0.91), 0.99 (95% CI = 0.78-1.26), and 0.88 (95% CI = 0.62-1.25), respectively. An essential tremor SNP (rs3794087 of SLC1A2) is associated with a decreased risk of PD in the Eastern Han Chinese population, while rs9652490 (LINGO1) and rs17590046 (PPARGC1A) do not show an association. Show less

Fuzhong buffalo, a native breed of Guangxi Zhuang Autonomous Region, is traditionally used as a draft animal to provide farm power in the rice cultivation. In addition, the Fuzhong buffalo also prepared for the bullfighting festival organized by the locals. The detection of the selective signatures in its genome can help in elucidating the selection mechanisms in its stamina and muscle development of a draft animal. In this study, we analyzed 27 whole genomes of buffalo (including 15 Fuzhong buffalo genomes and 12 published buffalo genomes from Upper Yangtze region). The ZHp, ZFst, π-Ratio, and XP-EHH statistics were used to identify the candidate signatures of positive selection in Fuzhong buffalo. Our results detected a set of candidate genes involving in the pathways and GO terms associated with the response to exercise (e.g., ALDOA, STAT3, AKT2, EIF4E2, CACNA2D2, TCF4, CDH2), immunity (e.g., PTPN22, NKX2-3, PIK3R1, ITK, TMEM173), nervous system (e.g., PTPN21, ROBO1, HOMER1, MAGI2, SLC1A3, NRG3, SNAP47, CTNNA2, ADGRL3). In addition, we also identified several genes related to production and growth traits (e.g., PHLPP1, PRKN, MACF1, UCN3, RALGAPA1, PHKB, PKD1L). Our results depicted several pathways, GO terms, and candidate genes to be associated with response to exercise, immunity, nervous system, and growth traits. The selective sweep analysis of the Fuzhong buffalo demonstrated positive selection pressure on potential target genes involved in behavior, immunity, and growth traits, etc. Our findings provided a valuable resource for future research on buffalo breeding and an insight into the mechanisms of artificial selection. Show less

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines Show less

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK. Show less

Liver plays an essential role in regulating lipid metabolism, and chronically disturbed hepatic metabolism may cause obesity and metabolic syndrome, which may lead to non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates long non-coding RNAs (lncRNAs) play an important role in energy metabolism. Here, we investigated the role of lncRNA H19 in hepatic lipid metabolism and its potential association with NAFLD. We found that H19 was up-regulated in oleic acid-induced steatosis and during the development of high-fat diet (HFD)-induced NAFLD. Exogenous overexpression of H19 in hepatocytes induced lipid accumulation and up-regulated the expression of numerous genes involved in lipid synthesis, storage and breakdown, while silencing endogenous H19 led to a decreased lipid accumulation in hepatocytes. Mechanistically, H19 was shown to promote hepatic steatosis by up-regulating lipogenic transcription factor MLXIPL. Silencing Mlxipl diminished H19-induced lipid accumulation in hepatocytes. Furthermore, H19-induced lipid accumulation was effectively inhibited by PI3K/mTOR inhibitor PF-04691502. Accordingly, H19 overexpression in hepatocytes up-regulated most components of the mTORC1 signalling axis, which were inhibited by silencing endogenous H19. In vivo hepatocyte implantation studies further confirm that H19 promoted hepatic steatosis by up-regulating both mTORC1 signalling axis and MLXIPL transcriptional network. Collectively, these findings strongly suggest that H19 may play an important role in regulating hepatic lipid metabolism and may serve as a potential therapeutic target for NAFLD. Show less

Deoxynivalenol (DON) is a major mycotoxin from the trichothecene family of mycotoxins produced by Fusarium fungi. It can cause a variety of adverse effects on human and farm animal health. Here, we determined the effect of DON on the Class III phosphatidylinositol 3-kinase (PIK3C3)/beclin 1/B cell lymphoma-2 (Bcl-2) pathway in PC12 cells and the relationship between autophagy and apoptosis. The effects of DON were evaluated based on the apoptosis ratio; the typical indicators of autophagy, including cellular morphology, acridine orange- and monodansylcadaverine-labeled vacuoles, green fluorescent protein-microtubule associated protein 1 light chain 3 (LC3) localization, and LC3 immunofluorescence; and the expression of key autophagy-related genes and proteins, that is, PIK3C3, beclin 1, Bcl-2, LC3, and p62. The relationship between autophagy and apoptosis was analyzed by western blot analysis and flow cytometry. DON-induced PC12 cell morphological changes and autophagy significantly. PIK3C3, beclin 1, and LC3 increased in tandem with the DON concentration used; Bcl-2 and p62 expression decreased as DON concentrations increased. Moreover, the PIK3C3/beclin 1/Bcl-2 signaling pathway played a role in DON-induced autophagy. Our findings suggest that DON can induce autophagy by activating the PIK3C3/beclin 1/Bcl-2 signaling pathway and that autophagy may play a positive role in reducing DON-induced apoptosis. Show less

Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growth factors. PAQR3 is a newly discovered tumor suppressor that also regulates autophagy induced by nutrient starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit the AKT: thymoma viral proto-oncogene; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG: Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC: Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6: ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI: tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation resistance associated. Show less

GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both Show less

Kinesin superfamily protein 3C (KIF3C), a motor protein of the kinesin superfamily, is expressed in the central nervous system (CNS). Recently, several studies have suggested that KIF3C may act as a potential therapeutic target in solid tumors. However, the exact function and possible mechanism of the motor protein KIF3C in glioma remain unclear. In this study, a variety of tests including CCK-8, migration, invasion, and flow cytometry assays, and western blot were conducted to explore the role of KIF3C in glioma cell lines (U87 and U251). We found that overexpression of KIF3C in glioma cell lines promoted cell proliferation, migration, and invasion and suppressed apoptosis, while silencing of KIF3C reversed these effects. Ectopic KIF3C also increased the expression of N-cadherin, vimentin, snail, and slug to promote the epithelial-mesenchymal transition (EMT). Mechanistically, overexpression of KIF3C increased the levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (p-AKT). These responses were reversed by KIF3C downregulation or AKT inhibition. Our results indicate that KIF3C promotes proliferation, migration, and invasion and inhibits apoptosis in glioma cells, possibly by activating the PI3K/AKT pathway Show less

Breast cancer (BC) is one of the most lethal malignant tumors and the leading cause of cancer-related death worldwide. Although early diagnostic techniques for BC have been well developed, 40% of cases are still diagnosed at the advanced stage, while for BC patients with distant metastases, the 5-year survival rate is usually lower than 30%. The Snail family, generally regarded as transcriptional repressors, has been indicated to be an essential prognostic factor in malignant tumors. However, limited data exist on public databases concerning the prognostic value of individual Snail family members in BC, especially SNAI3. Data from public databases including cBioPortal for Cancer Genomics, Gene Expression Omnibus, UCSC Xena Browser, and Human Protein Atlas (HPA) were downloaded. Based on the Kaplan¬-Meier plotter platform, correlation of the three members of the Snail family and prognosis in BC were analyzed. Individual Snail family members and their co-expressed genes were respectively enriched on different pathways and biological processes via the functional enrichment analysis (FunRich) tool. High SNAI1 mRNA expression was associated with shorter distant metastasis-free survival (DMFS) in all BC patients regardless of PAM50 subtype. Conversely, high SNAI3 mRNA expression was associated with longer DMFS. Although the presence of SNAI2 expression was significantly associated with DMFS in the whole cohort, no significant correlation was found in patients with luminal A or HER2 subtype. For patients with the most diverse clinicopathological features, high SNAI1 expression was associated with poor survival, with the converse being true for SNAI3. However, the impact on prognosis of patients with different clinicopathological features produced by SNAI2 expression was inconclusive. Furthermore, we discovered that SNAI1 or SNAI2 and their co-expressed genes frequently enriched receptor tyrosine kinase (RTK) signaling and integrin-related pathways which mainly functioned on epithelial-mesenchymal transition and were further involved in several processes of signal transduction and cell communication. Furthermore, as SNAI3, along with its co-expressed genes, enriched immune-related pathways, it may thus play a role in mediating the immune system. Our analysis revealed that SNAI1 mRNA expression may potentially be a negative prognostic factor, whereas SNAI3 mRNA was associated with positive prognosis in BC. Therefore, the assessment of SNAI1 and SNAI3 expression may be valuable for predicting prognosis in BC patients. Show less

Epithelial homeostasis plays an essential role in maintaining endometrial function. But the epithelial role in endometrial fibrosis has been less studied. Previously, we showed that ectopic expression of ΔNp63α is associated with fibrosis process and epithelial dysfunction in endometria of patients with intrauterine adhesions (IUAs). Since ΔNp63α is profoundly involved in maintaining the epithelial homeostasis, we hereby focused on its roles in regulating the function and phenotype of endometrial epithelial cells (EECs) in context of endometrial fibrosis. We identified a typical type 2 epithelial-to-mesenchymal transition (EMT) in EECs from IUA patients and this process was induced by the forced expression of ΔNp63α in EECs. In transcriptomic analysis, we found that diverse signaling pathways regulated by ΔNp63α were involved in pro-EMT. We demonstrated that the DUSP4/GSK-3β/SNAI1 pathway was critical in transducing the pro-EMT signals initiated by ΔNp63α, while bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis both in vitro and in vivo by blocking DUSP4/GSK3β/SNAI1 pathway. Taken together, our findings are important to understand the molecular mechanisms of endometrial fibrosis and to provide potential therapeutic targets. Show less

Sine oculis homeobox homolog 4 (SIX4), a member of the SIX family, play important role in the development and construction of vertebrate tissues and organs. There is very little known about the function of SIX4 in cancer cells. Herein, we investigated whether SIX4 promote cancer metastasis in addition to its direct role in breast cancer cells. Our study showed that the expression of SIX4 was profoundly increased in breast cancer tissues, and the high expression of SIX4 correlated strongly with distant metastasis and poor prognosis. Functional experiments demonstrated that SIX4 obviously promoted the cell migration and invasion of breast cancer cells, and up-regulated the expression of EMT mesenchymal marker, down-regulated the epithelial molecules by Snai1 induction Show less

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was induced in hypoxia and participated in cancer development. However, the role of PLOD2 in endometrial carcinoma remains unclear. To explore the influences and regulation mechanism of PLOD2 in endometrial carcinoma under hypoxic condition. The small interfering RNA (siRNA) targeting to PLOD2 and pcDNA3.1-PLPD2 were transfected to endometrial carcinoma cells to alter PLOD2 expression. Cell proliferation ability was determined by colony formation assay. Wound healing assay used to detect cell migration ability. Transwell invasion assay was used to detect cell invasion ability. PLOD2 and Hypoxia-inducible factor-1α (HIF-1α) were induced by hypoxia. Down-regulation of PLOD2 did not affect endometrial carcinoma cell proliferation ability, while inhibited cell migration, invasion under hypoxic condition. Besides, down-regulation of PLOD2 increased the levels of γ-catenin and E-cadherin and decreased levels of Fibronectin and Snail under hypoxic condition. Down-regulation of PLOD2 also inactivated Src and phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) signaling under hypoxic condition. The promoting effects of PLOD2 overexpression on migration, invasion and epithelial-mesenchymal transition (EMT) of endometrial carcinoma cells were reversed by Akt inhibitor (MK2206) under hypoxic condition. PLOD2 expression was increased in endometrial carcinoma cells under hypoxic condition. PLOD2 modulated migration, invasion, and EMT of endometrial carcinoma cells via PI3K/Akt signaling. PLOD2 may be a potential therapeutic target for endometrial carcinoma. Show less

Although the early diagnosis of prostate cancer (PCa) enhances life expectancy with a 5-year survival rate of 100 %, metastasized-PCa is the fundamental reason for death by PCa, hence requires an advanced and target-directed treatment strategy. Metastasis is considered to be initiated with the epithelial-mesenchymal transition (EMT) event in which tumor cells change their epithelial characteristics into mesenchymal form and exacerbates the cancer progression. Herein, we investigated the effect and mechanism of resveratrol function in PCa cell proliferation and migration and reported that TNF-receptor associated factor 6 (TRAF6), an unconventional E3 ligase, is a key mediator of resveratrol function to inhibit PCa cell growth and proliferation and targeted for lysosomal degradation by resveratrol. MTT and cell counting demonstrated that resveratrol inhibited the viability and proliferation in DU145 and PC3 cells. Resveratrol (50 μM) mediated the degradation of TRAF6 which in turn facilitated repression of the NF-κB pathway. Also, wound healing and transwell migration assays and level of EMT-related proteins showed that resveratrol used TRAF6, at least in part to inhibit cell migration. Overexpression of TRAF6 augmented EMT in PCa by upregulating the expression of transcription factor SLUG. Moreover, TRAF6 overexpression was closely associated with EMT process through the NF-κB pathway. Our exploration exhibited that resveratrol may inhibit EMT through the TRAF6/NF-κB/SLUG axis. Altogether, this study represents that TRAF6 acts as an intermediary of resveratrol action to suppress PCa cell proliferation and migration, and concerns future attention to obtain as a therapeutic target for the treatment of PCa. Show less

Activation of the epithelial-to-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with colorectal cancer contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine-specific demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer and enhances cell migration. In this study, we determine that LSD1 expression is significantly elevated in patients with colorectal cancer with mutation of the catalytic subunit of PI3K, Show less

Highly expressed G protein-coupled receptor 81 (GPR81), a receptor for lactate, is emerging as a critical regulator of tumor growth and metastasis. However, the mechanistic basis for its highly expression in cancer cells remains elusive. Here we report that tumor-derived lactate transcriptionally regulates GPR81 expression. We demonstrated that the transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). Mechanistically, lactate upregulates transcriptional factor Snail and induces the assembly of Snail/EZH2/STAT3 complex. Within this ternary complex, STAT3 activity is strongly enhanced. Consequently, the activated STAT3 by lactate directly binds GPR81promoter and activates its expression. These findings shed light on the transcriptional mechanism by which GPR81 expression is regulated in cancer cells, and provides mechanistic insight into how aberrant signaling and continually high lactate levels due to metabolic switch may yield a feed-forward/self-enabling loop to promote tumor progression. Show less