Microbiota regulation in constipation and colorectal cancer.

The relevance of constipation to the development and progression of colorectal cancer (CRC) is currently a controversial issue. Studies have shown that changes in the composition of the gut microbiota, a condition known as ecological imbalance, are correlated with an increasing number of common human diseases, including CRC and constipation. CRC is the second leading cause of cancer-related deaths worldwide, and constipation has been receiving widespread attention as a risk factor for CRC. Early colonoscopy screening of constipated patients, with regular follow-ups and timely intervention, can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC. As an important regulator of the intestinal microenvironment, the gut microbiota plays a critical role in the onset and progression of CRC. An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression, with alterations inducing changes in the expression of host genes, metabolic regulation, and local and systemic immunological responses. Furthermore, constipation greatly affects the composition of the gut microbiota, which in turn influences the susceptibility to intestinal diseases such as CRC. However, the crosstalk between the gut microbiota, constipation, and CRC is still unclear.

Blue rubber bleb nevus syndrome complicated with disseminated intravascular coagulation and intestinal obstruction: A case report.

BACKGROUND: Blue rubber bleb nevus syndrome is a rare vascular malformation syndrome with unclear etiopathogenesis and noncurative treatments. It is characterized by multiple vascular malformations of the skin, gastrointestinal tract, and other visceral organs. The most common symptoms are intermittent gastrointestinal bleeding and secondary iron deficiency anemia, thus requiring repeated blood transfusions and hospitalizations. It is easily missed and misdiagnosed, and there is no specific treatment. CASE SUMMARY: We report a case of blue rubber bleb nevus syndrome combined with disseminated intravascular coagulation and efficacy of treatment with argon plasma coagulation under enteroscopy and sirolimus. A 56-year-old female patient was admitted to the hospital with 3-year history of fatigue and dizziness that had aggravated over the past 10 d with melena. The patient had a history of repeated melena and multiple venous hemangiomas from childhood. After treatment with argon plasma coagulation combined with sirolimus for nearly 8 wk, the patient's serum hemoglobin increased to 100 g/L. At the 12-mo follow-up, the patient was well with stable hemoglobin (102 g/L) and no recurrent intestinal bleeding. CONCLUSION: Argon plasma coagulation and sirolimus may be an efficacious and safe treatment for blue rubber bleb nevus syndrome, which currently has no recommended treatments.

Cronkhite-Canada syndrome: An investigation in clinical features and pathogenesis.

OBJECTIVE: This study aimed to investigate the clinical features and potential pathogenesis of a rare nonhereditary polyposis syndrome, Cronkhite-Canada syndrome (CCS). METHODS: Medical records of eight patients with CCS who were admitted to our hospital from January 2005 to November 2019 were reviewed. Transcriptome profiling was performed in one patient to investigate its difference between gastric polyp tissue and normal mucosa. Differentially expressed genes (DEGs) were determined for functional analysis. The expression of inhibin beta A (INHBA) was further assessed by using immunohistochemistry. RESULTS: All patients presented with gastrointestinal polyposis, accompanied by diarrhea, skin hyperpigmentation, hair loss and nail dystrophy. Hyperplastic polyps were observed in seven patients, tubular adenoma in two, inflammatory polyps in one and hamartomatous polyps in one, respectively. All patients underwent comprehensive treatment and five achieved clinical remission. A total of 2107 DEGs, including 1265 upregulated and 842 downregulated, were found in the gastric polyp. Gene ontology analysis showed that upregulated genes were significantly enriched in the positive regulation of cell proliferation, epithelium development and angiogenesis. A protein-protein interaction analysis suggested that INHBA was at the center of the interaction network and might play an important role in CCS. Immunohistochemistry confirmed that INHBA expression was upregulated in CCS gastric polyps. CONCLUSIONS: CCS is a rare disease and its diagnosis mainly depends on typical clinical manifestations, endoscopic findings and histological features. INHBA upregulation may contribute to its pathogenesis.

Targeted Drug-Loaded Chemical Probe Staining Assay to Predict Therapy Response and Function as an Independent Pathological Marker.

Multi-targeted kinase inhibitors, such as sorafenib, have been used in various malignancies, but their efficacy in clinical applications varies among individuals and lacks pretherapeutic prediction measures. We applied the concept of "click chemistry" to pathological staining and established a drug-loaded probe staining assay. We stained the cells and different types of pathological sections and demonstrated that the assay was reliable. We further verified in cells, cell-derived xenograft model, and clinical level that the staining intensity of the probe could reflect drug sensitivity. The stained samples from 300 patients who suffered from hepatocellular carcinoma and used the sorafenib probe also indicated that staining intensity was closely related to clinical information and could be used as an independent marker without undergoing sorafenib therapy for prognosis. This assay provided new ideas for multi-target drug clinical trials, pre-medication prediction, and pathological research.

Hsp90ß promotes aggressive vasculogenic mimicry via epithelial-mesenchymal transition in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor. Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. Hsp90ß promotes endothelial cell-dependent angiogenesis in HCC. However, the relationship between Hsp90ß and VM formation is unclear. In this study, we found that Hsp90ß is positively correlated with VM and EMT marker proteins in HCC tissues and promotes tube formation, cell migration, and invasion in vitro. Hsp90ß interacts with Twist1 and promotes its deubiquitination and stabilization to nuclear translocation and enhances the VE-cadherin promoter activity. Results of in vitro analysis indicate that Hsp90ß enhances the tumor VM in tumor-burdened mice, and the Hsp90 inhibitor NVP-BEP800 suppresses VM formation by releasing Hsp90ß and Twist1 interaction. This study provides a potential antitumor therapy for inhibiting VM by targeting Hsp90ß in HCC.

Salidroside improves the hypoxic tumor microenvironment and reverses the drug resistance of platinum drugs via HIF-1α signaling pathway.

BACKGROUND: Hypoxia commonly occurs in solid tumors. The hypoxia in the center of solid tumors considerably decreases the chemosensitivity of tumor cells and induces epithelial-mesenchymal transition (EMT) as well as drug resistance of antitumor drugs. METHODS: Here, the effects of salidroside (Sal) combined with platinum drugs on human hepatocellular carcinoma were examined in vitro and in vivo. We investigated the antitumor effects of Sal by inhibiting the drug resistance and explained its mechanism in inhibiting tumor growth. FINDINGS: The results showed that Sal co-administration reverses the drug resistance of platinum drugs and suppressed metastasis induced by the hypoxic tumor microenvironment. Sal promoted the degradation of HIF-1α. In conclusion, Sal significantly increased the sensitivity to platinum drugs and inhibited hypoxia-induced EMT in hepatocellular carcinoma (HCC) through inhibiting HIF-1α signaling pathway. INTERPRETATION: Therefore, Sal may be an effective platinum drug sensitizer that can improve the chemotherapeutic efficacy in patients with HCC.

Protease-activated receptor-1 (PAR1) promotes epithelial-endothelial transition through Twist1 in hepatocellular carcinoma.

BACKGROUND: Tumor cells transfer into endothelial cells by epithelial-endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial-mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear. METHODS: Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed. RESULTS: This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors. CONCLUSION: PAR1 promotes EET through Twist1 in HCC.

Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma.

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.Significance: A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg Cancer Res; 78(15); 4150-62. ©2018 AACR.

Derepression of co-silenced tumor suppressor genes by nanoparticle-loaded circular ssDNA reduces tumor malignancy.

The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes KLF17, CDH1, and LASS2 had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.

Apigenin inhibits colonic inflammation and tumorigenesis by suppressing STAT3-NF-κB signaling.

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. Here, we investigated the effects of apigeninin inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Apigenin effectively inhibited ulcerative colitis, a type of IBD, and CAC. Apigenin decreased myeloperoxidase (MPO), inflammatory cytokine and COX-2 levels, and it attenuated inflammatory cell infiltration in treated colon tissues as compared to untreated model colon tissues. Apigenin also reduced NF-κB and STAT3 activity in vitro and in vivo, thereby inhibiting inflammation and inflammation-induced carcinogenesis. Thus apigenin appears to inhibit inflammation and inflammation-induced carcinogenesisin IBD and CAC by suppressing STAT3-NF-κB signaling.

Dihydroartemisinin inhibits EMT induced by platinum-based drugs via Akt-Snail pathway.

Artemisinin and its derivatives exhibit a high activity against a range of cancer cell types both in vitro and in vivo. In clinical practice, platinum-based anti-cancer chemotherapy is widely used to treat tumors. However, a large proportion of patients receiving these treatments will relapse because of metastasis and drug resistance. The purpose of this study is to explore the combinational anti-metastatic effect of platinum-based drugs and dihydroartemisinin (DHA). Both DDP and oxaliplatin (OXA) at low doses could induce epithelial-mesenchymal transition (EMT) in HCC. Meanwhile, co-administration of DHA could enhance DDP and OXA chemosensitivity in HCC and reverse drug resistance. DHA reversed the morphological changes induced by DDP or OXA and reversed the changes in EMT biomarkers induced by DDP and OXA in HCC in vitro and in vivo via AKT-Snail signaling. DHA significantly increased platinum-based drug sensitivity and suppressed EMT induced by platinum-based drugs via AKT-Snail signaling in HCC. DHA is expected to become the new adjuvant for chemotherapy.

Sesquiterpene binding Gly-Leu-Ser/Lys-"co-adaptation pocket" to inhibit lung cancer cell epithelial-mesenchymal transition.

Sesquiterpene lactones (SL) have a wide range of applications in anti-tumor and anti-inflammatory therapy. However, the pharmacological mechanism of such substances is not clear. In this study, parthenolide (PTL) was used as an example to explore the anti-tumor effect of natural molecules and their common mechanism. We showed that PTL inhibited the proliferation and migration by reverse EMT via the ERK2/NF-κB/Snail pathway in vivo and in vitro. Interestingly, Multiple potential targets of PTL contain a Gly-Leu-Ser/Lys-"co-adaptation pocket". This inspiring us analogies of PTL may also bind to these target proteins and play a similar function. Significantly, the Concept of co-adaptation pocket may help to increase the selectivity of drug research and development.

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.

Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma.

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by PLC and Bel-7402 human HCC cells. It also suppressed tumor growth in PLC cell xenografts without altering body weight, thereby prolonging survival. Apigenin reduced Snai1 and NF-κB expression, reversed increases in epithelial-mesenchymal transition (EMT) marker levels, increased cellular adhesion, regulated actin polymerization and cell migration, and inhibited invasion and migration by HCC cells. Apigenin may therefore inhibit EMT by inhibiting the NF-κB/Snail pathway in human HCC.

Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells.

The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.