The sclerotia of Polyporus umbellatus Fries is widely used to promote urination and prevent dampness.Our previous studies systematically demonstrated that ergosta‐4,6,8,22‐tetraen‐3‐one isolated from Polyporus umbellatus Fries showed significant antitumor, diuretic, and renoprotective effects.Our recent study demonstrated that ergone inhibited NF‐κB signaling and α‐SMA expression in 5/6 nephrectomised and unilateral ureteral obstruction rats.The Wnt signaling pathway is an evolutionarily conserved developmental signaling cascade that plays a critical role in regulating organ development and tissue homeostasis. Leucine‐rich repeat‐containing G protein‐coupled receptor 5 is a novel functional marker in glioma stem cells that promotes EMT by activating the Wnt/β‐catenin signaling pathway.Sry‐like high‐mobility group box 8 regulated cancer stem‐like properties and cisplatin‐induced EMT by the Wnt/β‐catenin signaling pathway in tongue squamous cell carcinoma.In addition,stackable planters bone marrow mesenchymal stromal cells suppressed EMT by inhibiting the Wnt/β‐catenin signaling pathway in silica‐induced pulmonary fibrosis.
Our previous study showed the activation of the canonical Wnt/β‐catenin signaling pathway accompanied by the upregulation of proinflammatory and pro‐oxidative protein expression in the NF‐κB signaling pathway and downregulation of the anti‐inflammatory Nrf2 signaling pathway in patients with chronic kidney disease compared with the Nrf2 signaling pathway in healthy controls.Many compounds inhibit the Wnt signaling pathway, and these compounds may suppress EMT in cancer and fibrosis .FH535, a β‐catenin/Tcf inhibitor, not only increased radio‐sensitivity but also suppressed EMT in the radio resistant KYSE‐150R esophageal cancer cell line, which indicated that inhibitors of the Wnt signaling pathway might be effective anticancer agents with the potential to be anticancer drugs.In addition, it was reported that FH535 alleviated multiple types of cancer, including colorectal cancer, gastric cancer, and hepatocellular carcinoma.Isoquercitrin, a bio-active flavonoid from Bidens bipinnata L., inhibited the Wnt/β‐catenin signaling pathway and hepatocyte growth factor/scatter factor‐induced EMT in NBT‐II cells.In addition, salinomycin was previously used as an antibiotic and also showed significant anticancer activity by suppressing EMT.Salinomycin‐inhibited EMT by suppressing the Wnt/β‐catenin signaling pathway in epithelial ovarian cancer cells, indicating that small molecules targeting the Wnt/β‐catenin signaling pathway might have anticancer properties by reversing EMT.Poria cocos is a well‐known fungus that exhibits an effective therapeutic effect to improve kidney function in clinic.Our previous studies have confirmed that extracts of the surface layer of Poria cocos show remarkable antihyperlipidemic, diuretic, and renoprotective effects.
Recently, our group isolated more than 90 triterpenoid compounds from the surface layer of Poria cocos, some of which exhibited significant anti-fibrotic properties.New triterpenoids, including poricoic acid ZC, poricoic acid ZD, and poricoic acid ZE, significantly down regulated the expression of Wnt1, active β‐catenin, Snail, Twist, MMP‐7, PAI‐1, and FSP1 in HK‐2 cells induced by TGF‐β1 and angiotensin II and mice with unilateral ureteral occlusion. Moreover, new triterpenoids, including poricoic acid ZG and poricoic acid ZH, improved renal fibrosis by targeting the phosphorylation of Smad3 signaling and the Wnt/β‐catenin signaling pathwa . Alismatis rhizome , the dried rhizome of Alisma orientale Juzep, exhibited diuretic, antihyperlipidemic, and renoprotective effects that were also confirmed by our previous studies.Our recent study demonstrated that triterpenoid was the main component of AR,and further study showed that the novel tetracyclic triterpenoid 25‐O‐methylalisol F inhibited EMT by suppressing the Wnt/β‐catenin signaling pathway as well as the phosphorylation of Smad3 signaling in both NRK‐52E and NRK‐49F cells . Additionally, it was also observed that ergone inhibited extracellular matrix accumulation in HK‐2 cells and attenuated podocyte injury through inhibiting the activation of the Wnt/β‐catenin signaling pathway induced byangiotensin II.Taken together, these data indicate that tetracyclic triterpenoid and steroid compounds show significant anti-fibrotic properties in renal fibrosis.Akt is a serine/threonine‐specific protein kinase that plays a key role in various cellular activities. Many cellular signals are transduced through the Akt signaling pathway, and Akt is involved in EMT in cooperation with other proteins. For example, tripartite motif‐containing 14 is an oncogene that regulated EMT and the metastasis of human gastric cancer by activating Akt signaling.M3 muscarinic acetylcholine receptors regulated EMT, perineural invasion, and metastasis in cholangiocarcinoma via the Akt pathway.
Canopy homologue 2 promoted EMT via activating the Akt/GSK3 pathway in non–small‐cell lung cancer.In addition, Akt also promoted EMT cooperation with miRNAs. MiR‐944 inhibited EMT and the metastasis of gastric cancer by the metastasis‐associated in colon cancer 1 /Met/Akt signaling pathway.MiR‐1296 inhibited EMT and the metastasis of hepatocellular carcinoma via the serine/threonine‐protein kinase 1/PI3K/Akt signaling pathway.Taken together, these data suggest that Akt plays a key role in EMT cellular signal transduction and that targeting Akt might be an effective approach to treat fibrosis and tumors . Simvastatin is a 3‐hydroxy‐3‐methylglutaryl coenzyme A inhibitor that was originally used to treat cardiovascular diseases. Recently, it was reported that simvastatin had a therapeutic effect in several cancers. The administration of simvastatin suppressed EMT through the phosphatase and tensin homologue /PI3K/Akt pathway in EC9706‐R cells, suggesting a new therapeutic function for simvastatin in cancers.Trichostatin A, a histone deacetylase inhibitor, is an antifungal antibiotic. In addition to its antibiotic properties, trichostatin A alleviated EMT in bleomycin‐ induced lung injury in mice via inhibiting the Akt signaling pathway.Ubenimex inhibits multiple proteases, including arginyl aminopeptidase, leukotriene A4 hydrolase, alanyl aminopeptidase, and leucyl/cysteinyl aminopeptidase, a membrane dipeptidase used to treat acute myelocytic leukemia and lymphedema. Ubenimex alleviated acquired sorafenib resistance in renal cell carcinoma via suppressing the Akt pathway.Luteolin is widely distributed in plants and has shown anti inflammatory, antioxidant, antimicrobial, and antitumor properties. Luteolin attenuated TGF‐β1‐induced EMT by mediating the PI3K/Akt/NF‐κB‐Snail pathway in lung cancer cells. In addition, luteolin attenuated the progression of gastric cancer by reversing EMT via the Notch signaling pathway.Moreover, luteolin also suppressed the metastasis of triple‐negative breast cancer via blocking EMT by the down regulation of β‐catenin.Furthermore, luteolin suppressed EMT by down regulating the expression of cyclic AMP‐responsive element binding protein 1175 in colorectal cancer cells.Collectively, luteolin showed therapeutic effects in both tissue fibrosis and tumors through various signaling pathways and might be a promising candidate to treat fibrosis and tumors. α‐Mangostin derived from the pericarp of the mangosteen fruit has been shown to have various cellular functions, such as arresting the cell cycle, inhibiting cell viability, inducing apoptosis, and differentiation, reducing inflammation and decreasing adhesion.
α‐Mangostin suppressed viability and EMT by downregulating the PI3K/Akt pathway in pancreatic cancer.Icaritin, a hydrolytic product of icariin that is isolated from members of the Epimedium genus, induced the trans‐differentiation of embryonic stem cells into cardiomyocytes, prevented steroid‐ associated osteonecrosis and stimulated neuronal differentiation.Icaritin inhibited invasion and EMT via targeting the PTEN/Akt/HIF‐1α signaling pathway.As a highly conserved cell signaling system, the Notch signaling pathway is widely involved in cell proliferation and differentiation during embryonic and adult development. Extensive studies have demonstrated that the Notch signaling pathway is also critical for EMT in tumorigenesis and fibrogenesis. The over expression of Notch1‐induced EMT in PC‐3 cells, and claudin‐1 contributed to EMT by the Notch signaling pathway in human bronchial epithelial cells.In addition, Notch and TGF‐β1 generated a reciprocal positive regulatory loop and cooperatively regulated EMT in epithelial ovarian cancer cells,stackable flower pots which provided new insight into the mechanism of EMT.Moreover, miR‐34a downregulation induced by hypoxia enhanced EMT via the Notch signaling pathway in tubular epithelial cells, which indicated that the Notch signaling pathway is critical for EMT during fibrosis.These cases suggest that a targeted intervention in the Notch signaling pathway might be an effective strategy to treat cancer and fibrosis. DAPT, a γ‐secretase inhibitor, decreased the expression of Snail and vimentin and increased E‐cadherin expression in two oral squamous cell carcinoma cell lines, Tca8113 and CAL27, indicating that the targeted inhibition of the Notch signaling pathway might be a new therapeutic strategy to treat cancer. Another γ‐secretase inhibitor, RO4929097, not only inhibited EMT, invasion, and metastasis in cervical cancer HeLa and CaSki cells but also exerted significant therapeutic effects in patients with recurrent malignant glioma, cervical and colon cancer and advanced solid tumors in clinical trials.3,6‐Dihydroxyflavone is ubiquitous in vegetables and fruits and blocks EMT in breast cancer cells through suppressing the Notch signaling pathway.Moreover, luteolin inhibited EMT in gastric cancer by the Notch signaling pathway.In addition, emodin is a main bioactive component of Polygonum cuspidatum that suppressed EMT in alveolar epithelial cells via the Notch signaling pathway. Therefore, it is a promising prospect in treating pulmonary fibrosis.Furthermore, berberine was isolated from Berberis vulgaris and reversed EMT by blocking the Notch/Snail signaling pathway in mice with diabetic nephropathy.The RAS signaling pathway not only regulates blood pressure and fluid balance but also is involved in many kinds of diseases, including cancer and fibrosis. Recently, emerging evidence has suggested that the RAS signaling pathway plays a key role in EMT during fibrosis and tumorigenesis. Angiotensin II promoted EMT by the interaction between hematopoietic stem cells and the stromal cell‐derived factor‐1/CXR4 axis in intrahepatic cholangiocarcinoma.In addition, the overexpression of angiotensin II type 1 receptor induced EMT and promoted tumorigenesis in human breast cancer cells, and the silencing of angiotensin II type 1 receptor suppressed EMT that was induced by high glucose through inactivating the mTOR/p70s6k signaling pathway in the human proximal tubular epithelial HK‐2cell line.
Based on these results, it was suggested that suppressing RAS might be an effective therapy to treat cancer and fibrosis. Losartan is an AT1R antagonist that improved renal fibrosis by suppressing EMT in rats with hyperglycemia.Although many RAS inhibitors showed beneficial effects in tumors and fibrosis, few were reported to inhibit EMT in the treatment of cancer and fibrosis.MiRNAs are endogenous small noncoding RNAs that bind the 3′‐untranslated region of messenger RNAs to regulate gene expression. Recently, many miRNAs have been found to promote or suppress EMT in fibrosis and tumors. For example, miRNA‐497/Wnt3a/c‐Jun regulated growth and EMT, and miR‐497 served as a tumor suppressor in glioma cells.Moreover, miR‐205 inhibited tumor growth, invasion, and EMT via targeting semaphorin 4C in hepatocellular carcinoma.Furthermore, the upregulation of miR‐183‐5p induced apoptosis and inhibited EMT, proliferation, invasion, and migration by the downregulation of ezrin in human endometrial cancer cells.Collectively, EMT is inhibited by many miRNAs, including miR‐145, miR‐497, miR‐145‐5p, miR‐138, miR‐200a, miR‐200b, miR‐655, miR‐30‐5p, and miR‐32.In addition, EMT is also promoted by many miRNAs, including miR‐221, miR‐222, miR‐214‐3p, and miR‐181a.The flavonoids rhamnetin from cloves, berries and cirsiliol from Cirsium lineare Sch.‐Bip. showed anti inflammatory and antitumor properties. Both rhamnetin and cirsiliol induced radio‐senitization and inhibited EMT by miR‐34a/Notch1 signaling in non–small‐cell lung cancer cells.Quercetin alleviated TGF‐β1‐induced fibrosis in HK‐2 cells via downregulating miR‐21 expression and upregulating PTEN and TIMP metallopeptidase inhibitor 3 expression.Sophocarpine from Sophora alopecuroides L. inhibited tumor progression and reversed EMT by targeting miR‐21 in head and neck cancer.In addition, sophocarpine exerted a profound antitumor effect through inhibiting EMT induced by TGF‐β. Zerumbone from Zingiber zerumbet Smith exhibited anti‐inflammatory and anticancer properties. Recently, it was reported that zerumbone inhibited the β‐catenin pathway via miR‐200c to block EMT and cancer stem cells.In addition, nicotine upregulated FGFR3 and RB1 and promoted EMT by the downregulation of miR‐99b and miR‐192 in non–small‐cell lung cancer cells.50 Moreover, osthole alleviated EMT‐mediated metastasis by inhibiting miR‐23a‐3p.Furthermore, resveratrol inhibited proliferation, invasion, and EMT via the upregulation of miR‐200c in HCT‐116 colorectal cancer cells.RNA‐binding proteins such as RNA‐binding Fox protein 2 , epithelial splicing regulatory protein 1 , and ESRP2 control the splicing of many gene transcripts and splice nascent RNAs to functionally and structurally different miRNAs to regulate the process of EMT. For example, bleomycin inhibited ESRP1 expression, leading to the increased alternative splicing of FGFR2 to its mesenchymal isoform IIIc, which induced EMT in lung fibrosis.In addition, over expressed ESRP1 contributed to EMT in ovarian cancer, inducing a cell‐specific variant of CD44 and a protein‐enabled homologue.Moreover, Rbfox2 was upregulated during the EMT, and the depletion of Rbfox2 suppressed the expression of mesenchymal marker genes.Several studies have revealed that small molecules regulate the expression of RNA‐binding proteins to mediate EMT. For example, caffeine, an alkaloid in tea and coffee, reduced p53α expression and upregulated p53β expression through altering the expression of serine/arginine‐rich splicing factor 3 to regulate EMT.Both tissue fibrosis and tumors lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Mounting studies have demonstrated that EMT plays a critical role in fibrosis and tumors, suggesting that drugs targeting EMT may be an effective therapy against fibrosis and tumors. Although TGF‐β1 is a potent inducer of EMT, new targets are needed due to the controversial role of TGF‐β1, which has been shown to have multiple beneficial roles in various bio-activities. As summarized above, myriad mediators, including many transcription factors , signaling pathways , RNA‐binding proteins and miRNAs, regulate EMT.