• Carcinogenesis
• Dysbiosis
• Extraintestinal cancers
• Inflammation
• Microbiota

• Humans
• Dysbiosis/complications
• Dysbiosis/microbiology
• Neoplasms/etiology
• Neoplasms/pathology
• Neoplasms/microbiology
• Gastrointestinal Microbiome
• Animals

• 82160546 National Science Foundation of China
• 82460116 National Science Foundation of China
• 20202BBG73027 Science Foundation of Jiangxi Province
• 20242BAB26116 Science Foundation of Jiangxi Province
• JXSQ2023201020 Foundation of Jiangxi Province for Distinguished Scholars
• 20183021 Science and Technology Plan Fund of Jiangxi Health Commission
• 20202ACBL206017 Science and Technology Department of Jiangxi Province
• GJJ210185 Education Department of Jiangxi Province

• Colorectal cancer (CRC)
• Gut barrier
• Lipopolysaccharides (LPS)
• Metastatic disease
• Tight junctions (TJs)

• RAGE
• RAGE inhibitor
• cancer
• end products
• targeted therapy

• antibiotics
• cancer treatment
• dysbiosis
• microbiome
• prevention
• probiotics

• LPS
• MyD88
• NF-ĸB/MAPK
• colorectal cancer
• inflammatory

• Bacteria
• Gut microbiome
• cancer
• dysbiosis
• immunoglobulin
• short chain fatty acids

• JNK
• LPS
• PRP4
• TLR4
• decursin
• inflammation

Trichosanthes tricuspidata Lour., also known as T. palmata Roxb, T. bracteata Lam., T. puber Blume, and Modecca bracteata, is a vine belonging to the Cucurbitaceae family (English name: redball snake gourd). Distributed in China, South and East Asia, and tropical Australia, it has been traditionally used as a medicinal plant for its antifever, laxative, anthelmintic properties and for migraine treatment. In this paper, we examined the effects of Trichosanthes tricuspidata Lour. ethanol extract (Tt-ME) in vitro and in vivo. To confirm the effects of Tt-ME on inflammatory responses, we conducted experimental analyses including level of nitric oxide (NO) production, RT-PCR, and immunoblotting and using a HCl/EtOH-induced gastritis animal model. Tt-ME attenuated the release of NO and decreased mRNA levels of inducible NO synthase (iNOS), TNF-α, and IL-6 in lipopolysaccharide- (LPS-) induced macrophages in a concentration-dependent manner. Tt-ME time-dependently suppressed nuclear translocation of nuclear factor kappa B (NF-κB) subunits p50 and p65, activator protein (AP-1) subunits c-Fos and c-Jun, and STAT3 transcriptional activity by inhibiting nuclear translocation of p50, p65, c-Fos, c-Jun, and STAT3. Tt-ME significantly downregulated NF-κB, MAPK, and JAK2 signaling by targeting Syk, Src, and IRAK1 protein kinases. Furthermore, matrix metalloproteinase-9 (MMP-9) expression and cell migration were observed to be downregulated by Tt-ME in LPS-activated macrophages. In vivo studies on Tt-ME also produced similar trends in Hcl/EtOH-induced gastritis mouse models by inhibiting proinflammatory cytokines and the inflammatory signaling pathway. Our results strongly suggest that Tt-ME exerted anti-inflammatory activity in LPS-stimulated macrophages and mouse models of acute inflammatory disease.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of cancer deaths in the word. Hepatitis B virus (HBV) infection plays an important role in the development of HCC. However, the mechanisms by which HBV integration affects host cells remain poorly understood. HepG2.2.15 cell line is derived from HCC cell line HepG2 with stable transfection HBV expression. In this study, HepG2.2.15 cells showed decreased proliferation, G1 cell cycle arrest and increased apoptosis, when compared to HepG2 cells. HBV capture sequencing was conducted in both genome and transcriptome level, followed by RNA expression sequencing in HepG2.2.15. Here, CAMSAP2/CCDC12/DPP7/OR4F3 were found to be targets for HBV integration in both genome and transcriptome level, accompanied by alteration in their expression when compared to HepG2. Among these genes, DPP7 was the only one gene with HBV integration into its exon, meanwhile DPP7 expression level was also downregulated in HepG2.2.15 as compared to HepG2. Furthermore, DPP7 knockdown resulted in increased apoptosis through upregulation of the Bax/Bcl2 ratio in HepG2 cells. Our results suggest that HBV integration of DPP7 was involved in cell apoptosis.

• HepG2.2.15
• Hepatitis B virus
• apoptosis
• cell cycle
• proliferation
• viral integration

• ERK/MAPK
• Hydroxysafflor yellow A
• PI3K/AKT/mTOR
• lipopolysaccharide
• non-small cell lung cancer

Inflammation has been known to be linked to invasion or metastasis of breast cancer, which has poor prognosis, although the regulatory mechanism remains to be undiscovered. Here we show that T-LAK cell-originated protein kinase (TOPK) mediates pro-inflammatory endotoxin lipopolysaccharide (LPS)-induced breast cancer cell migration and invasion. The mRNA or protein level of TOPK, toll- like receptor4 (TLR4), interleukin (IL)-6, vascular endothelial growth factor (VEGF) or matrix metalloproteinase9 (MMP9) genes related to TLR4 signaling or tumor progression was induced by LPS treatment in MCF7 breast cancer cells, but the induction was abolished by stable knocking down of TOPK in MCF7 cells. Also, TOPK depletion decreased LPS-induced phosphorylation of p38, but not ERK and JNK among mitogen-activated protein kinases (MAPKs). On the other hand, we revealed that TOPK is essential for transcriptional activity of NF-κB or MMP9 promoter triggered by LPS. The induced promoter activity of NF-κB or MMP9 but not AP-1 was inhibited by knocking down of TOPK. Furthermore, we demonstrated that inhibitor of TOPK or MMP9 as well as MMP9 siRNA efficiently blocked LPS-induced migration or invasion of breast cancer cell lines. Interestingly, both of expression of TOPK and TLR4 were markedly increased in high-grade breast cancer. Collectively, we conclude that TOPK functions as a key mediator of LPS/TLR4-induced breast cancer cell migration and invasion through regulation of MMP9 expression or activity, implying a potential role of TOPK as a therapeutic target linking LPS-induced inflammation to breast cancer development.

• TOPK
• breast cancer
• invasion
• matrix metalloproteinase

Lipopolysaccharide (LPS) exists in the outer membrane of Gram-negative bacteria. Colorectal normal epithelium and colorectal cancer cells in situ are continuously exposed to LPS from intestinal bacteria, while little is known about the influence of LPS on colorectal cancer progression and metastasis. In this study, we investigated the potential role of LPS on colorectal cancer progression and metastasis as well as the underlying mechanisms. We measured higher LPS concentration in colorectal cancer tissues and even higher LPS concentration in colorectal cancer tissues with lymph node metastasis. LPS significantly enhanced cancer cell motility and promoted human dermal lymphatic endothelial cells' (HDLECs') capacity of tube-like formation in vitro, as well as accelerates lymphangiogenesis and lymph node metastasis in nude mice. Furthermore, we demonstrated LPS notably increased the expression of VEGF-C in a time-dependent and concentration-dependent manner. VEGF-C is a key regulator for lymphangiogenesis and lymph node metastasis. By constructing lentivirus-mediated shVEGF-C cells, VEGF-C down-regulation suppressed LPS' promotive effect on cancer cell motility and HDLEC tube-like formation capacity. In addition, we found TLR4- NF-κB/JNK signal pathways were important for LPS to increase VEGF-C expression. All these result suggested a critical role for LPS in migration, invasion, lymphangiogenesis and lymph node metastasis of colorectal cancer, providing evidence that LPS increased VEGF-C secretion to promote cell motility and lymphangiogenesis via TLR4- NF-κB/JNK signaling.

• VEGF-C
• cell motility
• colorectal cancer
• lipopolysaccharide
• lymphatic metastasis

• Carcinogenesis
• Immune regulation
• Inflammation
• Microbial metabolites
• Traditional Chinese Medicine

• Carcinogenesis
• Immune regulation
• Inflammation
• Microbial metabolites
• Traditional Chinese Medicine

• Anti-Bacterial Agents/therapeutic use
• Gastrointestinal Microbiome/drug effects
• Gastrointestinal Neoplasms/microbiology
• Gastrointestinal Neoplasms/prevention & control
• Gastrointestinal Tract/microbiology
• Humans

• R01 CA190122 NCI NIH HHS

• NF-κB
• SDF-1α/CXCR4 axis
• colorectal cancer
• epithelial-mesenchymal transition
• lipopolysaccharides

Helicobacter pylori (H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases.

• Hepatocellular carcinoma
• Cirrhosis
• Hepatic encephalopathy
• Helicobacter pylori
• Nonalcoholic fatty liver disease
• Fibrosis
• Pancreatitis
• Pancreatic cancer
• Diabetes mellitus
• Metabolic syndrome

• Hepatocellular carcinoma
• Invasion
• Jun N-terminal kinase
• Lipopolysaccharide
• Toll-like receptor 4

• Extraintestinal disorders
• Gastroduodenal diseases
• Helicobacter pylori
• Host factors
• Virulence factor

• Cardiovascular Diseases/complications
• Colorectal Neoplasms/complications
• Comorbidity
• Genomic Islands
• Helicobacter Infections/microbiology
• Helicobacter Infections/physiopathology
• Helicobacter pylori/genetics
• Hematologic Diseases/complications
• Humans
• Immune System
• Insulin Resistance
• Pancreatic Neoplasms/complications
• Peptic Ulcer/complications
• Risk Factors
• Skin Diseases/complications
• Stomach Neoplasms/complications
• Treatment Outcome
• Virulence Factors

• xiaochaihu decoction (xchd)
• ethanol
• cci₄
• hepatocellular carcinoma (hcc)
• liver depression and spleen deficiency (ldsd)
• oxidative stress
• nitrosative stress
• lipopolysaccharid
• catecholamines
• alkaline phosphatase (alp)

• Alkaline Phosphatase/metabolism
• Animals
• Brain/drug effects
• Brain/pathology
• Brain Chemistry/drug effects
• Carbon Tetrachloride/toxicity
• Catecholamines
• Drug Stability
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/pharmacology
• Ethanol/toxicity
• Intestinal Mucosa/metabolism
• Intestines/drug effects
• Intestines/pathology
• Linear Models
• Lipopolysaccharides
• Liver/chemistry
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Liver Neoplasms, Experimental/chemically induced
• Liver Neoplasms, Experimental/metabolism
• Male
• Malondialdehyde/metabolism
• Mice
• Organ Size/drug effects
• Organ Specificity
• Oxidative Stress/drug effects
• Peroxynitrous Acid/metabolism

Surgery induced inflammation is a potent promoter of tumour recurrence and metastasis in colorectal cancer. The recently discovered family of Nox enzymes represent a major source of endogenous reactive oxygen species (ROS) and are now heavily implicated in tumour cell metastasis. Interestingly, Nox enzymes can be ‘purposefully’ activated by inflammatory cytokines and growth factors which are present in abundance in the peri-operative window. As colon cancer cells express Nox enzymes and Toll-like receptor 4 (TLR-4), we hypothesised that LPS may potentiate the ability of colon cancer cells to metastasise via Nox enzyme mediated redox signalling. In support of this hypothesis, this paper demonstrates that LPS induces a significant, transient increase of endogenous ROS in SW480, SW620 and CT-26 colon cancer cells. This increase in LPS-induced ROS activity is completely abrogated by a Nox inhibitor, diphenyleneiodonium (DPI), Nox1 siRNA and an NF-κB inhibitor, Dihydrochloride. A significant increase in Nox1 and Nox2 protein expression occurs following LPS treatment. Inhibition of NF-κB also attenuates the increase of Nox1 and Nox2 protein expression. The sub-cellular location of LPS-induced ROS generation lies mainly in the endoplasmic reticulum. LPS activates the PI3K/Akt pathway via Nox generated ROS and this signal is inhibited by DPI. This LPS activated Nox mechanism facilitates a significant increase in SW480 colon cancer cell adhesion to collagen I, which is inhibited by DPI, Nox1 siRNA and a PI3K inhibitor. Altogether, these data suggest that the LPS-Nox1 redox signalling axis plays a crucial role in facilitation of colon cancer cell adhesion, thus increasing the metastatic potential of colon cancer cells. Nox1 may represent a valuable target in which to prevent colon cancer metastasis.

• Cell Adhesion/drug effects
• Cell Line, Tumor
• Colonic Neoplasms/immunology
• Colonic Neoplasms/pathology
• Colorectal Neoplasms/immunology
• Humans
• Lipopolysaccharides/pharmacology
• Membrane Glycoproteins/biosynthesis
• NADPH Oxidase 1
• NADPH Oxidase 2
• NADPH Oxidases/antagonists & inhibitors
• NADPH Oxidases/biosynthesis
• NF-kappa B/physiology
• Neoplasm Metastasis/physiopathology
• Onium Compounds/pharmacology
• Phosphatidylinositol 3-Kinases/physiology
• Proto-Oncogene Proteins c-akt/physiology
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects
• Toll-Like Receptor 4/physiology
• Up-Regulation

• toll-like receptor 4
• epithelial-mesenchymal transition
• lipopolysaccharide
• human hepatocellular carcinoma

• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Movement
• Cells, Cultured
• Coculture Techniques
• Culture Media, Conditioned/chemistry
• Female
• Hepatic Stellate Cells/metabolism
• Hepatitis B/complications
• Hepatitis B virus
• Hepatocytes/metabolism
• Humans
• Inflammation
• Interleukin-6/biosynthesis
• Kaplan-Meier Estimate
• Liver Neoplasms/metabolism
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Membrane Glycoproteins/agonists
• Membrane Glycoproteins/antagonists & inhibitors
• Membrane Glycoproteins/biosynthesis
• Middle Aged
• Myeloid Cells/immunology
• Myeloid Cells/metabolism
• Myofibroblasts/metabolism
• Prognosis
• Receptors, Immunologic/agonists
• Receptors, Immunologic/antagonists & inhibitors
• Receptors, Immunologic/biosynthesis
• Triggering Receptor Expressed on Myeloid Cells-1
• Tumor Necrosis Factor-alpha/biosynthesis

Recent studies have emphasized causative links between microRNAs (miRNAs) deregulation and tumor development. In hepatocellular carcinoma (HCC), more and more miRNAs were identified as diagnostic and prognostic cancer biomarkers, as well as additional therapeutic tools. This study aimed to investigate the functional significance and regulatory mechanism of the miR-199a2/214 cluster in HCC progression.

In this study, we showed that miR-214, as well as miR-199a-3p and miR-199a-5p levels were significantly reduced in the majority of examined 23 HCC tissues and HepG2 and SMMC-7721 cell lines, compared with their nontumor counterparts. To further explore the role of miR-214 in hepatocarcinogenesis, we disclosed that the ER stress-induced pro-survival factor XBP-1 is a target of miR-214 by using western blot assay and luciferase reporter assay. Re-expression of miR-214 in HCC cell lines (HepG2 and SMMC-7721) inhibited proliferation and induced apoptosis. Furthermore, ectopic expression of miR-214 dramatically suppressed the ability of HCC cells to form colonies in vitro and to develop tumors in a subcutaneous xenotransplantation model of the BALB/c athymic nude mice. Moreover, reintroduction of XBP-1s attenuated miR-214-mediated suppression of HCC cells proliferation, colony and tumor formation. To further understand the mechanism of the miR-199a/214 cluster down-expression in HCC, we found that thapsigargin (TG) and tunicamycin (TM) or hypoxia-induced unfolded protein response (UPR) suppresses the expression of the miR-199a/214 cluster in HCC cells. By promoter analysis of the miR-199a2/214 gene, we conjectured NFκB as a potential negative regulator. We further found that UPR and LPS-induced NFκB activation suppressed miR-199a2/214 transcription, and this suppression was reversed by NFκB inhibition in HCC cells.

Our study suggest that modulation of miR-214 levels may provide a new therapeutic approach for cancer treatment and revealed that UPR may offer a new explanation for why the miR-199a/214 cluster were down-regulated in the progression in HCC.

• Animals
• Apoptosis
• Carcinoma, Hepatocellular/pathology
• DNA-Binding Proteins
• Disease Progression
• Down-Regulation/genetics
• Down-Regulation/physiology
• Endoplasmic Reticulum/pathology
• Humans
• Mice
• MicroRNAs/genetics
• MicroRNAs/physiology
• NF-kappa B/metabolism
• Regulatory Factor X Transcription Factors
• Stress, Physiological
• Transcription Factors
• Transplantation, Heterologous
• Unfolded Protein Response
• X-Box Binding Protein 1

To investigate the effect of HBV on the proliferative ability of host cells and explore the potential mechanism.

MTT, colony formation assay and tumourigenicity in nude mice were performed to investigate the effect of HBV on the proliferative capability of host cells. In order to explore the potential mechanism, cell cycle and apoptosis were analysed. The cell cycle genes controlling the G1/S phase transition were detected by immunohistochemistry, westernblot and RT-PCR.

HepG2.2.15 cells showed decreased proliferation ability compared to HepG2 cells. G1 phase arrest was the main cause but was not associated with apoptosis. p53, p21 and total retinoblastoma (Rb) were determined to be up-regulated, whereas cyclinE was down-regulated at both the protein and mRNA levels in HepG2.2.15 cells. The phosphorylated Rb in HepG2.2.15 cells was decreased.

Our results suggested that HBV inhibited the capability of proliferation of HepG2.2.15 cells by regulating cell cycle genes expression and inducing G1 arrest.