Correction: Interaction between laminin-5γ2 and integrin ß1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins.

The original version of this Article contained an error in the author affiliations. Affiliation number 4 incorrectly read "Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Disease, Tianjin Institute of Digestive Disease". It should be "Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China".

Interaction between laminin-5γ2 and integrin ß1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins.

Colorectal cancer (CRC) is a common cancer type and a threat to human health. Tumor budding (TB) is the presence of a single cancer cell or clusters of up to five cancer cells prior to the invasive front of an aggressive carcinoma and is an independent prognosis factor for CRC. The molecular mechanism of TB is still unclear, and drugs that inhibit this process are still in the blank stage. This study found that TBs exhibit characteristics of partial EMT with a decreased expression of E-cadherin and no substantial differences in the expression of N-cadherin and vimentin. We also observed the interaction of integrin with extracellular matrix components, laminin-5γ2 (LN-5γ2), play essential roles in the TB of CRC. We then verified that the interaction between LN-5γ2 and integrin ß1 promotes the TB of CRC via the activation of FAK and Yes-associated proteins (YAP). A natural drug monomer, cucurbitacin B, was screened using virtual screening methods for the interaction interface of proteins. We found that this monomer could block the interaction interface between LN-5γ2 and integrin ß1 and substantially inhibit the TB of CRC cells via inactivation of YAP. This study provides new insights into the mechanism of TB mechanism and the development of drugs targeting the TB of CRC.

Thymidine phosphorylase promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect.

Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE-Cad, VEGFR1, and VEGFR2 in vitro and in vivo. The TP inhibitor tipiracil reduced the effect of TP on promoting HCC VM formation and metastasis. Hence, TP, when transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through the pentose Warburg effect and contributes to tumor progression.

Therapeutic effects of lentinan on inflammatory bowel disease and colitis-associated cancer.

In this study, we investigated the therapeutic potential of lentinan in mouse models of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Lentinan decreased the disease activity index and macroscopic and microscopic colon tissue damage in dextran sulphate sodium (DSS)-induced or TNBS-induced models of colitis. High-dose lentinan was more effective than salicylazosulfapyridine in the mouse models of colitis. Lentinan decreased the number of tumours, inflammatory cell infiltration, atypical hyperplasia and nuclear atypia in azoxymethane/DSS-induced CAC model. It also decreased the expression of pro-inflammatory cytokines, such as IL-13 and CD30L, in IBD and CAC model mice possibly by inhibiting Toll-like receptor 4 (TLR4)/NF-κB signalling and the expression of colon cancer markers, such as carcinoembryonic antigen, cytokeratin 8, CK18 and p53, in CAC model mice. In addition, lentinan restored the intestinal bacterial microbiotal community structure in IBD model mice. Thus, it shows therapeutic potential in IBD and CAC model mice possibly by inhibiting TLR4/NF-κB signalling-mediated inflammatory responses and disruption of the intestinal microbiotal structure.

Oleanolic Acid Inhibits Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Promoting iNOS Dimerization.

Oleanolic acid exhibits extensive pharmacologic activities and takes significant antitumor effects. Its pharmacologic mechanism, however, still remained to be further clarified. In this study, we demonstrated that oleanolic acid attenuated the migration and invasion abilities, resulting in the suppression of the epithelial-mesenchymal transition (EMT) process in liver cancer cells, and inhibited the tumor growth of the peritoneal lymphocytes-bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of oleanolic acid. We confirmed that oleanolic acid could promote the dimerization of iNOS, activating it, and subsequently increasing the production of nitric oxide. Further experiments indicated that oleanolic acid promoted the nitration of specific proteins and consequently suppressed their EMT-related biological functions. Furthermore, it has been confirmed that oleanolic acid enhanced the antitumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacologic mechanism of the antitumor effect oleanolic acid, and the importance of nitric oxide synthetase as a therapeutic target for liver cancer treatment.

Selenium-lentinan inhibits tumor progression by regulating epithelial-mesenchymal transition.

BACKGROUND: Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. METHODS: Lentinan, an antitumor polysaccharide extracted from Lentinus edodes, was conjugated with seleninic acid to be transformed into ester (Se-lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se-lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial-mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. RESULTS: Se-lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se-lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se-lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. CONCLUSION: The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier.

Polyphyllin I suppresses the formation of vasculogenic mimicry via Twist1/VE-cadherin pathway.

Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells and is related to the metastasis and poor prognosis of many cancer types, including hepatocellular carcinoma (HCC). Thus far, no effective drugs have been developed to target VM. In this study, patients with liver cancer exhibited reduced VM in tumor tissues after treatment with Rhizoma Paridis. Polyphyllin I (PPI), which is the main component of Rhizoma Paridis, inhibited VM formation in HCC lines and transplanted hepatocellular carcinoma cells. Molecular mechanism analysis showed that PPI impaired VM formation by blocking the PI3k-Akt-Twist1-VE-cadherin pathway. PPI also displayed dual effects on Twist1 by inhibiting the transcriptional activation of the Twist1 promoter and interfering with the ability of Twist1 to bind to the promoter of VE-cadherin, resulting in VM blocking. This study is the first to report on the clinical application of the VM inhibitor. Results may contribute to the development of novel anti-VM drugs in clinical therapeutics.

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 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.