EIF4A3-negatively driven circular RNA ß-catenin (circß-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis.

BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.

LncRNA-NEF suppressed oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer through epigenetically inactivating MEK/ERK signaling.

A major cause of oxaliplatin chemoresistance in colorectal cancer (CRC) is acquired epithelial-mesenchymal transition (EMT) in cancer cells, making the cancer cells easy to metastasis and recurrence. LncRNA Neighboring Enhancer of FOXA2 (lncRNA-NEF) has been characterized as a tumor suppressor to mediate cancer metastasis in multiple cancer types. However, whether it mediated the drug resistance remains unknown. In the present study, an oxaliplatin-resistant CRC cell line (SW620R) was established and lncRNA-NEF was obviously down-regulated in this resistant cell line. The further loss and gain-of-function studies demonstrated that this lncRNA suppressed oxaliplatin resistance as well as EMT programme in vitro and inhibited metastasis in vivo. Mechanistically, lncRNA-NEF epigenetically promoted the expression of DOK1 (Downstream of Tyrosine kinase 1), a negative regulator of MEK/ERK signaling, by disrupting DNA methyltransferases (DNMTs)-mediated DNA methylation. DOK1, in turn, induced the inactivation of MEK/ERK signaling, forming the lncRNA-NEF/DOK1/MEK/ERK regulatory axis to mediate oxaliplatin resistance in CRC. Collectively, our work reveals the critical function of lncRNA-NEF in mediating the oxaliplatin chemotherapy resistance in CRC, and provides a promising therapeutic strategy for CRC patients with oxaliplatin resistance.

Linc-ROR drive adriamycin resistance by targeting AP-2α/Wnt/ß-catenin axis in hepatocellular carcinoma.

Adriamycin is widely used as a chemotherapeutic strategy for advanced hepatocellular carcinoma (HCC). However, the clinical response was disappointing because of the acquired drug resistance with long-term usage. Revealing the underlying mechanism could provide promising therapeutics for the drug-resistant patients. The recently identified linc-ROR (long intergenic non-protein-coding RNA, regulator of reprogramming) has been found to be an oncogene in various cancers, and it also demonstrated to mediate drug resistance and metastasis. We thereby wonder whether this lincRNA could mediate adriamycin chemoresistance in HCC. In this study, linc-ROR was found to be upregulated in adriamycin-resistant HCC cells. And its overexpression accelerated epithelial-mesenchymal transition (EMT) program and adriamycin resistance. Conversely, its silence suppressed EMT and made HCC cells sensitize to adriamycin in vitro and in vivo. Further investigation revealed that linc-ROR physically interacted with AP-2α, mediated its stability by a post-translational modification manner, and sequentially activated Wnt/ß-catenin pathway. Furthermore, linc-ROR expression was positively associated with ß-catenin expression in human clinical specimens. Taken together, linc-ROR promoted tumorigenesis and adriamycin resistance in HCC via a linc-ROR/AP-2α/Wnt/ß-catenin axis, which could be developed as a potential therapeutic target for the adriamycin-resistant patients.

Berberine inhibits tumour growth in vivo and in vitro through suppressing the lincROR-Wnt/ß-catenin regulatory axis in colorectal cancer.

BACKGROUND: Berberine, a non-prescription medicine clinically applied for diarrhoea and gastroenteritis. Recent studies have demonstrated that it possesses anti-tumour properties in colorectal cancer, but the exact molecular mechanism remains obscure. OBJECTIVES: To elucidate the underly molecular mechanisms of berberine in colorectal cancer from a perspective of epigenetics, and tried to explore the role of lincROR-Wnt/ß-catenin molecular axis in the berberine induced the anti-tumour activity in colorectal cancer. METHODS: The effects of berberine on cell growth, cell cycle and apoptosis were examined in CRC cells. The in vivo effect of berberine on tumour growth was investigated using a xenograft mice model. Moreover, lincROR and Wnt/ß-catenin signalling were detected by luciferase activity, qRT-PCR and western blotting assays. KEY FINDINGS: Berberine suppressed cell growth in vitro via inducing cell cycle arrest and apoptosis in CRC cell, and inhibited tumourigenesis in vivo. LincROR was significantly down-regulated by berberine, inducing the inactivation of the canonical Wnt/ß-catenin signalling, meanwhile, the overexpression of lincROR partially reversed the suppressive effects on tumour growth and Wnt/ß-catenin signalling induced by berberine. CONCLUSIONS: Berberine inhibits tumour growth partially via regulating the lincROR-Wnt/ß-catenin regulatory axis, which provides a strategy for the design of anti-tumour drugs for CRC patients after our advanced validation.

Icariside II suppressed tumorigenesis by epigenetically regulating the circß-catenin-Wnt/ß-catenin axis in colorectal cancer.

Icariside II, a flavonol glycoside, one of the major components of Traditional Chinese Medicine Herba epimedii. In the present study, we found that Icariside II suppressed the proliferation of CRC by inducing cell cycle arrest and apoptosis in vitro and inhibited tumor growth in vivo. The further mechanism investigation showed that Icariside II suppressed the expression of ß-catenin and led to the functional inactivation of Wnt/ß-catenin signaling. Circß-catenin was considered as a promising candidate for mediating the tumorigenesis and the activation of Wnt/ß-catenin signaling in CRC cells. Furthermore, Icariside II has been proven to suppress the biogenesis of circß-catenin via epigenetically targeting DNA methyltransferases (DNMTs) to decrease global DNA methylation levels in CRC cells. Taken together, our results indicated that Icariside II suppressed tumorigenesis by epigenetically silencing the activation of circß-catenin-Wnt/ß-catenin axis in colorectal cancer. More importantly, the information gained from this study suggest that Icariside II may have great potential to be developed as a therapeutic drug for CRC patients.

Baicalein mediates the anti-tumor activity in Osteosarcoma through lncRNA-NEF driven Wnt/ß-catenin signaling regulatory axis.

Background: Osteosarcoma (OS) is a common type of malignant bone tumor in adolescents with high risk of metastasis. However, the clinical management still remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely considered as an alternative treatment, and their extracts have proved to possess great potential for drug discovery. Baicalein (BA), the active pharmaceutical ingredient of rhizoma coptidis, was proved to have anti-tumor properties in OS, but the mechanism remains poorly understood. Methods: The potential anti-cancer effects on cell growth, cell cycle, apoptosis and migration were examined in OS cells. Moreover, the lncRNA-Neighboring Enhancer of FOXA2 (lncRNA-NEF) and Wnt/ß-catenin signaling were detected by qPCR and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using a xenograft mice model. Results: In the present study, BA was found to significantly suppress tumor growth in vitro and in vivo. And it was also found to inhibit the invasion and metastasis as well. As for the mechanism investigation, lncRNA-NEF was obviously upregulated by BA in OS cells, and thus induced the inactivation of Wnt/ß-catenin signaling. Moreover, lncRNA-NEF knockdown partially reversed the BA-induced anti-cancer activities; and successfully compensated the suppressive effect on Wnt/ß-catenin signaling. We therefore suggested that BA induced the inactivation of Wnt/ß-catenin signaling through promoting lncRNA-NEF expression. Conclusions: In conclude, our results demonstrated that BA suppressed tumor growth and metastasis in vitro and in vivo through an lncRNA-NEF driven Wnt/ß-catenin regulatory axis, in which lncRNA-NEF was upregulated by BA, and thus induced the inactivation of Wnt/ß-catenin signaling. The Translational potential of this article: The findings derived from this study validates the anti-cancer activity of BA in OS and provides a novel underlying mechanism, which suggest that BA may be a potential candidate to develop the effective drug for OS patients.

Gallic Acid Suppressed Tumorigenesis by an LncRNA MALAT1-Wnt/ß-Catenin Axis in Hepatocellular Carcinoma.

Gallic acid (3,4,5-trihydroxybenzoic acid; GA), a natural phenolic acid, is abundantly found in numerous natural products. Increasing evidence have demonstrated that GA plays anti-cancer roles in multiple cancers. However, its anti-tumor effects on hepatocellular carcinoma (HCC) and the underlying mechanism remain obscure. In the present study, we found that GA suppressed the in vitro cell viability and metastasis and inhibited the in vivo tumor growth of HCC cells. The underlying mechanism was further to investigate and it was showed that GA suppressed the expression of ß-catenin and led to the functional inactivation of Wnt/ß-catenin signaling. As a kind of significant regulators, the long noncoding RNA molecules (lncRNAs) have attracted widespread attentions for their critical roles in diverse biological process and human diseases. To further identify which lncRNA participated this GA-mediated process, several lncRNAs related to Wnt/ß-catenin signaling were chosen for examination of their expression profiling in the GA-treated HCC cells. Of which, Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) was the most promising candidate. And moreover, MALAT1 was significantly down-regulated by GA. Its overexpression partially reversed the GA-induced the inhibitory effects on cell proliferation and metastasis; and successfully abolished the suppressive effect of GA on Wnt/ß-catenin signaling. In conclusion, our results indicated that GA suppressed tumorigenesis in vitro and in vivo by the MALAT1-Wnt/ß-catenin signaling axis, suggesting that GA has great potential to be developed as a chemo-prevention and chemotherapy agent for HCC patients.

Apigenin promotes osteogenic differentiation of mesenchymal stem cells and accelerates bone fracture healing via activating Wnt/ß-catenin signaling.

Apigenin (API), a natural plant flavone, is abundantly found in common fruits and vegetables. As a bioactive flavonoid, API exhibits several activities including antiproliferation and anti-inflammation. A recent study showed that API could retard osteoporosis progress, indicating its role in the skeletal system. However, the detailed function and mechanism remain obscure. In the present study, API was found to promote osteogenic differentiation of mesenchymal stem cells (MSCs). And further investigation showed that API could enhance the expression of the critical transcription factor ß-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/ß-catenin signaling. Using a rat femoral fracture model, API was found to improve new bone formation and accelerate fracture healing in vivo. In conclusion, our data demonstrated that API could promote osteogenesis in vitro and facilitate the fracture healing in vivo via activating Wnt/ß-catenin signaling, indicating that API may be a promising therapeutic candidate for bone fracture repair.NEW & NOTEWORTHY1) API promoted osteogenic differentiation of human MSCs in vitro; 2) API facilitated bone formation and accelerated fracture healing in vivo; 3) API stimulated Wnt/ß-catenin signaling during osteogenesis of human MSCs.

H19-Wnt/ß-catenin regulatory axis mediates the suppressive effects of apigenin on tumor growth in hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. However, the effective pharmacological approaches remain scanty in clinical practice. As a bioactive flavonoid, apigenin (API) is enriched in common fruits and vegetables. Although pharmacological activities of API have been widely investigated, its biological function in HCC remains obscure. In the present study, we found that API strongly suppressed cell growth and induced apoptosis in HCC cells. Using a xenograft mice model, API was demonstrated to inhibit the in vivo tumor growth. It is known that the long non-coding RNA H19, which is frequently elevated in HCC, plays a vital role in mediating tumorigenesis and cancer progression. Our results demonstrated that H19 was down-regulated by API, and thereby induced the inactivation of the canonical Wnt/ß-catenin signaling. In conclusion, our results demonstrated that API was able to suppress tumor growth of HCC through H19-mediated Wnt/ß-catenin signaling regulatory axis, suggesting that API may be a promising candidate for developing novel therapeutic approaches against liver cancer.

LincROR Mediates the Suppressive Effects of Curcumin on Hepatocellular Carcinoma Through Inactivating Wnt/ß-Catenin Signaling.

As one of the leading causes of cancer-related death in the world, hepatocellular carcinoma (HCC) has continued to attract growing attention in recent decades. The use of traditional Chinese herbs in medicine has been practiced for thousands of years, and holds the potential of being a possible treatment for HCC. Curcumin, a bioactive ingredient derived from Curcuma longa, exhibits anti-tumor activity in various cancers. Although the effects of Curcumin on HCC have been elucidated, the underlying mechanism remains unclear. In the present study, Curcumin was demonstrated to inhibit the proliferation of HCC cells via inducing cell cycle arrest and apoptosis. Several previously reported lncRNAs related to tumorigenesis were chosen for examination of their expression profiles, and lincROR was found to be the most down-regulated in the Curcumin-treated HCC cells. Furthermore, Curcumin was found to decrease ß-catenin expression and induce the inactivation of Wnt/ß-catenin signaling. Therefore, Curcumin suppressed tumor growth through a lincROR/ß-catenin regulatory pattern. In conclusion, our results demonstrated that Curcumin suppressed the cell proliferation via the down-regulation of lincROR and inactivation of Wnt/ß-catenin signaling, suggesting that it may be a potential anti-cancer candidate for HCC patients with activated Wnt/ß-catenin signaling.

Urolithin B suppresses tumor growth in hepatocellular carcinoma through inducing the inactivation of Wnt/ß-catenin signaling.

Consumption of dietary ellagitannins (ETs) has been proven to benefit multiple chronic health disorders including cancers and cardiovascular diseases. Urolithins, gut microbiota metabolites derived from ETs, are considered as the molecules responsible for these health effects. Previous studies have demonstrated that urolithins exhibit antiproliferative effects on prostate, breast, and colon cancers. However, as for hepatocellular carcinoma (HCC), it remains elusive. Herein, we aim to investigate the function of urolithin B (UB), a member of urolithins family, in HCC. The effects of UB on cell viability, cell cycle and apoptosis were evaluated in HCC cells, and we found UB could inhibit the proliferation of HCC cells, which resulted from cell cycle arrest and apoptosis. Furthermore, UB could increase phosphorylated ß-catenin expression and block its translocation from nuclear to cytoplasm, thus inducing the inactivation of Wnt/ß-catenin signaling. Using a xenograft mice model, UB was found to suppress tumor growth in vivo. In conclusion, our data demonstrated that UB could inhibit the proliferation of HCC cells in vitro and in vivo via inactivating Wnt/ß-catenin signaling, suggesting UB could be a promising candidate in the development of anticancer drugs targeting HCC.