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Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7 Show less

10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF- Show less

Liver iron excess is observed in several chronic liver diseases and is associated with the development of hepatocellular carcinoma (HCC). However, apart from oxidative stress, other cellular mechanisms by which excess iron may mediate/increase HCC predisposition/progression are not known. HCC pathology involves epithelial to mesenchymal transition (EMT), the basis of cancer phenotype acquisition. Here, the effect of excess iron (holo-transferrin 0-2 g/L for 24 and 48 h) on EMT biomarkers in the liver-derived HepG2 cells was investigated. Holo-transferrin substantially increased intracellular iron. Unexpectedly, mRNA and protein expression of the epithelial marker E-cadherin either remained unaltered or increased. The mRNA and protein levels of metastasis marker N-cadherin and mesenchymal marker vimentin increased significantly. While the mRNA expression of EMT transcription factors SNAI1 and SNAI2 increased and decreased, respectively after 24 h, both factors increased after 48 h. The mRNA expression of TGF-β (EMT-inducer) showed no significant alterations. In conclusion, data showed direct link between iron and EMT. Iron elevated mesenchymal and metastatic biomarkers in HepG2 cells without concomitant decrement in the epithelial marker E-cadherin and altered the expression of the key EMT-mediating transcription factors. Such studies can help identify molecular targets to devise iron-related adjunctive therapies to ameliorate HCC pathophysiology. Show less

FGF signaling pathway is imperative for definitive endoderm (DE) differentiation from human embryonic stem cells (hESCs), which always accompanies an epithelial-to-mesenchymal transition (EMT) process. However, whether there is an association between FGF signaling and the EMT during DE formation in vitro has remained elusive. In the present study, we identify that several FGF family members were significantly activated during the differentiation of hESCs toward DE. Inhibition of FGF signaling by an efficient and selective inhibitor BGJ398 abolishes both the EMT and DE induction by blocking the activation of the zinc-finger transcription factor SNAI1 which is a direct transcriptional repressor of cell adhesion protein CDH1. In addition, cell proliferation is also severely influenced by attenuating the FGF signaling. Collectively, we propose that the FGF signaling promotes the DE formation through mediating the EMT and cell proliferation. Show less

Thyroid cancer incidence has increased worldwide; however, investigations of thyroid cancer-related factors as potential prognosis markers remain insufficient. Secreted proteins from the cancer secretome are regulators of several molecular mechanisms and are, thereby, ideal candidates for potential markers. We aimed to identify a specific factor for thyroid cancer by analyzing the secretome from normal thyroid cells, papillary thyroid cancer (PTC) cells, and anaplastic thyroid cancer cells using mass spectrometry (MS). Cathepsin B (CTSB) showed highest expression in PTC cells compared to other cell lines, and CTSB levels in tumor samples were higher than that seen in normal tissue. Further, among thyroid cancer patients, increased CTSB expression was related to higher risk of lymph node metastasis (LNM) and advanced N stage. Overexpression of CTSB in thyroid cancer cell lines activated cell migration by increasing the expression of vimentin and Snail, while its siRNA-mediated silencing inhibited cell migration by decreasing vimentin and Snail expression. Mechanistically, CTSB-associated enhanced cell migration and upregulation of vimentin and Snail occurred via increased phosphorylation of p38. As our results suggest that elevated CTSB in thyroid cancer induces the expression of metastatic proteins and thereby leads to LNM, CTSB may be a good and clinically relevant prognostic marker. Show less

Erythrocyte membrane protein band 4.1-like 3 (EPB41L3) is an important membrane skeletal protein that may interact with numerous membrane proteins. Loss of EPB41L3 is reported in multiple cancer types, and it is originally identified as a tumor suppressor. In this study, through analyzing expression profiling retrieved from the Gene Expression Omnibus (GEO) dataset, we find that EPB41L3 is upregulated in primary osteosarcoma (OS) and osteosarcoma cell lines. Importantly, EPB41L3 may promote osteosarcoma cell proliferation and suppress osteosarcoma cell migration and invasion. Reduced EPB41L3 leads to a decrease of E-cadherin as well as an increase of N-cadherin and Vimentin, implying a prominent epithelial-to-mesenchymal transition. Furthermore, we demonstrate that EPB41L3 inhibits the epithelial-to-mesenchymal transition through destabilizing the Snai1 protein, one of the most important transcription factors of the epithelial-to-mesenchymal transition process. Collectively, our study has first established the complex and vital roles of EPB41L3 and implicated EPB41L3 as a potential biomarker in osteosarcoma. Show less

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Biomarkers of the therapeutic efficacy of ICIs have been extensively investigated. In this study, we aimed to analyze whether molecular phenotypes of circulating tumor cells (CTCs) are associated with treatment responses and clinical outcomes in patients with R/M HNSCC treated with nivolumab. Peripheral blood samples were collected before treatment initiation and after four infusions of nivolumab. CTCs isolated by depletion of CD45-positive cells were analyzed to determine the expression of EPCAM, MET, KRT19, and EGFR using real-time quantitative polymerase chain reaction. CTC-positive samples were analyzed to determine the expression of PIK3CA, CCND1, SNAI1, VIM, ZEB2, CD44, NANOG, ALDH1A1, CD47, CD274, and PDCD1LG2. Of 30 patients treated with nivolumab, 28 (93.3%) were positive for CTCs. In 20 CTC-positive patients, molecular alterations in CTCs before and after nivolumab treatment were investigated. Patients with MET-positive CTCs had significantly shorter overall survival than those with MET-negative CTCs (p = 0.027). The expression level of CCND1 in CTCs of disease-controlled patients was significantly higher than that of disease-progressed patients (p = 0.034). In disease-controlled patients, the expression level of CCND1 in CTCs significantly decreased after nivolumab treatment (p = 0.043). The NANOG expression in CTCs was significantly increased in disease-controlled patients after nivolumab treatment (p = 0.036). Our findings suggest that the molecular profiling of CTCs is a promising tool to predict the treatment efficacy of nivolumab. Show less

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Metastasis and chemoresistance are regarded as the two leading causes of treatment failure and high mortality in CRC. Forkhead Box M1 (FOXM1) has been involved in malignant behaviors of cancer. However, the role and mechanism of FOXM1 in simultaneously regulating metastasis and chemoresistance of CRC remain poorly understood. Here, we found that FOXM1 was overexpressed in oxaliplatin- and vincristine-resistant CRC cells (HCT-8/L-OHP and HCT-8/VCR) with enhanced metastatic potential, compared with HCT-8 cells. FOXM1 overexpression increased migration, invasion and drug-resistance to oxaliplatin and vincristine in HCT-8 cells, while FOXM1 knockdown using shFOXM1 impaired metastasis and drug-resistance in HCT-8/L-OHP and HCT-8/VCR cells. Moreover, FOXM1 up-regulated Snail to trigger epithelial-mesenchymal transition-like molecular changes and multidrug-resistance protein P-gp expression, while silencing Snail inhibited FOXM1-induced metastasis and drug-resistance. We further identified that disheveled-2 (DVL2) was crucial for FOXM1-induced Snail expression, metastasis and chemoresistance. Furthermore, FOXM1 bound to DVL2, and enhanced nuclear translocation of DVL2 and DVL2-mediated transcriptional activity of Wnt/β-catenin known to induce Snail expression. In conclusion, FOXM1/DVL2/Snail axis triggered aggressiveness of CRC. Blocking FOXM1/DVL2/Snail pathway simultaneously inhibited metastasis and chemoresistance in CRC cells, providing a new strategy for successful CRC treatment. Show less

Diabetic cataract is a common complication of diabetes. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a key event in the development of diabetic cataracts. Metastasis-associated lung adenocarcinoma transcript 1 ( Show less

Autocrine transforming growth factor (TGF)β has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous Show less

The endoplasmic reticulum stress and the unfolded protein response are triggered following an imbalance between protein load and protein folding. Until recently, two possible outcomes of the unfolded protein response have been considered: life or death. We sought to substantiate a third alternative, dedifferentiation, mesenchymal shift, and activation of the antioxidant response by using typical endocrine cells, i.e. thyroid cells. The thyroid is a unique system both of endoplasmic reticulum stress (a single protein, thyroglobulin represents the majority of proteins synthesized in the endoplasmic reticulum by the thyrocyte) and of polarized epithelium (the single layer of thyrocytes delimiting the follicle). Following endoplasmic reticulum stress, in thyroid cells the folding of thyroglobulin was disrupted. The mRNAs of unfolded protein response were induced or spliced (X-box binding protein-1). Differentiation was inhibited: mRNA levels of thyroid specific genes, and of thyroid transcription factors were dramatically downregulated, at least in part, transcriptionally. The dedifferentiating response was accompanied by an upregulation of mRNAs of antioxidant genes. Moreover, cadherin-1, and the thyroid (and kidney)-specific cadherin-16 mRNAs were downregulated, vimentin, and SNAI1 mRNAs were upregulated. In addition, loss of cortical actin and stress fibers formation were observed. Together, these data indicate that ER stress in thyroid cells induces dedifferentiation, loss of epithelial organization, shift towards a mesenchymal phenotype, and activation of the antioxidant response, highlighting, at the same time, a new and wide strategy to achieve survival following ER stress, and, as a sort of the other side of the coin, a possible new molecular mechanism of decline/loss of function leading to a deficit of thyroid hormones formation. Show less

Cancer metastasis involves diverse cellular functions via bidirectional communications between intracellular and extracellular spaces. To achieve development of the anti-metastatic drugs, one needs to consider the efficacy and mode of action (MOA) of the drug candidates to block the metastatic potentials of cancerous cells. Rather than under two-dimensional environment, investigation of the metastatic potentials under three-dimensional environment would be much pharmaceutically beneficent, since it can mimic the in vivo tumor lesions in cancer patients, leading to allowance of drug candidates analyzed in the 3D culture systems to lower failure rates during the anti-metastatic drug development. Here we have reviewed on the analyses of metastatic potentials of certain cancer models in 3D culture systems surrounded with extracellular matrix proteins, which could be supported by TM4SF5- and/or EMT-mediated actions. We particularly focused the initial events of the cancer metastasis, such as invasive outgrowth and dissemination from the cancer cell masses, spheroids, embedded in the 3D gel culture systems. This review summarizes the significance of tetraspanin TM4SF5 and Snail1 that are related to EMT in the metastatic potentials explored in the 3D gel systems. Show less

Manganese (Mn) is an essential micronutrient. However, it is well established that Mn overexposure causes nervous system diseases. In contrast, there are few reports on the effects of Mn exposure on glomerular endothelium. In the present study, the potential effects of Mn exposure on glomerular endothelium were evaluated. Sprague Dawley rats were used as a model of Mn overexposure by intraperitoneal injection of MnCl Show less

Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. The overexpression of COUP-TFII has been observed in several types of malignancies. However, its role in ICC progression remains unclear. In this study, we found that the protein level of COUP-TFII was increased, but the mRNA level was unchanged in ICC tissues. High protein expression was positively associated with tumor size, lymph node metastasis, and poor prognosis in ICC patients. Furthermore, the overexpression of COUP-TFII promoted the proliferation, migration, and invasion of ICC cells in vitro and enhanced tumor growth and metastasis in nude mouse models. Mechanistic studies revealed that COUP-TFII induced epithelial-to-mesenchymal transition in ICC cells by upregulating Snail expression. Moreover, the activation of PI3K/AKT signaling led to the upregulation of COUP-TFII protein expression in ICC. Together, these findings indicate that COUP-TFII promotes epithelial-to-mesenchymal transition and metastasis in ICC and suggest that this protein is a potential target for adjuvant therapy for these patients. Show less

Kinesin superfamily protein 3C (KIF3C), a motor protein of the kinesin superfamily, is expressed in the central nervous system (CNS). Recently, several studies have suggested that KIF3C may act as a potential therapeutic target in solid tumors. However, the exact function and possible mechanism of the motor protein KIF3C in glioma remain unclear. In this study, a variety of tests including CCK-8, migration, invasion, and flow cytometry assays, and western blot were conducted to explore the role of KIF3C in glioma cell lines (U87 and U251). We found that overexpression of KIF3C in glioma cell lines promoted cell proliferation, migration, and invasion and suppressed apoptosis, while silencing of KIF3C reversed these effects. Ectopic KIF3C also increased the expression of N-cadherin, vimentin, snail, and slug to promote the epithelial-mesenchymal transition (EMT). Mechanistically, overexpression of KIF3C increased the levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (p-AKT). These responses were reversed by KIF3C downregulation or AKT inhibition. Our results indicate that KIF3C promotes proliferation, migration, and invasion and inhibits apoptosis in glioma cells, possibly by activating the PI3K/AKT pathway Show less

In recent years, pulmonary fibrosis caused by paraquat poisoning is still concerned. However, no effective drugs have been developed yet to treat paraquat-induced pulmonary fibrosis. The aim of our research is to investigate whether imrecoxib can inhibit paraquat-induced pulmonary fibrosis and its possible mechanism. Extraction of primary pulmonary fibrosis cells (PPF cells) in vitro by the method of trypsin digestion. RT-qPCR and western blot were employed to measure the transcription level and protein expression of EMT related markers in paraquat-induced A549 cells. MTT, wound-healing, and Transwell experiments were used to verify the effect of imrecoxib on the proliferation, migration, and invasion of PPF and HFL1 cells. Firstly, our results confirmed that paraquat can induce EMT and activate the NF- Imrecoxib can inhibit EMT of paraquat-induced A549 cells and alleviate paraquat-caused pulmonary fibrosis through the NF- Show less

Ultrasound-targeted microbubble destruction (UTMD) has been found to be an effective method for delivering microRNAs (miRNAs, miRs). The current study is aimed at discovering the potential anti-cancer effects of UTMD-mediated miR-206 on HCC. In our study, the expressions of miR-206 and peptidyl-prolyl MiR-206 expression was downregulated while PPIB expression was upregulated in HCC, and PPIB was recognized as a target gene of miR-206 in HCC tissues. UTMD-mediated miR-206 inhibited HCC cell migration and invasion while promoting apoptosis via regulating the expressions of proteins related to apoptosis, migration, and invasion by targeting PPIB. Our results suggested that the delivery of UTMD-mediated miR-206 could be a potential therapeutic method for HCC treatment, given its effects on inhibiting cell migration and invasion and promoting cell apoptosis. Show less

Epithelial-mesenchymal transition (EMT) or its reverse process mesenchymal-epithelial transition (MET) occurs in multiple physiological and pathological processes. However, whether an entire EMT-MET process exists and the potential function during human hematopoiesis remain largely elusive. Utilizing human pluripotent stem cell (hPSC)-based systems, it is discovered that while EMT occurs at the onset of human hematopoietic differentiation, MET is not detected subsequently during differentiation. Instead, a biphasic activation of mesenchymal genes during hematopoietic differentiation of hPSCs is observed. The expression of mesenchymal genes is upregulated during the fate switch from pluripotency to the mesoderm, sustained at the hemogenic endothelium (HE) stage, and attenuated during hemogenic endothelial cell (HEP) differentiation to hematopoietic progenitor cells (HPCs). A similar expression pattern of mesenchymal genes is also observed during human and murine hematopoietic development in vivo. Wnt signaling and its downstream gene SNAI1 mediate the up-regulation of mesenchymal genes and initiation of mesoderm induction from pluripotency. Inhibition of transforming growth factor- Show less

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β (TGF-β) superfamily, is a prognostic biomarker of cervical cancer. In addition, GDF15 has been reported to enhance the migration of colorectal cancer cells and liver cancer stem-like cells. However, the mechanism by which GDF15 promotes cervical cancer cell migration is not completely understood. Here, we report that GDF15 expression is enhanced in cervical cancer tissues, as well as in cultured cervical cancer cells. ShGDF15 transfection markedly inhibited expression of Vimentin, N-cadherin and Snail1, and resulted in up-regulation of E-cadherin expression in HT-3 and HeLa cells. Moreover, knockdown of GDF15 suppressed wound healing rate and reduced the number of invasive cells. Furthermore, knockdown of GDF15 significantly suppressed the expression of phosphorylated Smad2 and Smad3. The addition of TGF-β1 partially abolished the inhibitory effects of GDF15 knockdown on the migration and invasion of cervical cancer cells. In summary, we report here that GDF15 knockdown inhibits migration and invasion of cervical cancer cells in vitro through the TGF-β/Smad2/3/Snail1 pathway. Show less

Thymoquinone (TQ), the main active constituent of Nigella sativa seeds, has been shown to play a role in antioxidation, anti-inflammation, and antitumor. Recent studies have demonstrated that TQ contributes to the suppression of liver fibrosis. Abnormal activated epithelial-mesenchymal transition (EMT) promotes the activation of hepatic stellate cells (HSCs). However, whether the antifibrotic effects of TQ occur through inhibiting EMT is largely unknown. In this study, it was found that TQ ameliorated liver fibrosis and collagen accumulation in carbon tetrachloride (CCl Show less

Lung cancer always ranks first in the number of cancer deaths every year, accounting for 18.4% of total cancer deaths in 2018. Metastasis is the main cause of death in lung cancer patients. The identification of bioactive components of traditional Chinese medicine is very important for the development of novel reagents against non-small cell lung cancer (NSCLC). Rosthorin A has originated from Rabdosia rosthornii (Diels) Hara which excerpts from 'Chinese materia medica', and is known to have 'clear heat phlegm' properties in the folk. Little is known about the biological functions and mechanisms of Rosthorin A in cancer cells at present. The role of EMT in metastasis of a tumor cell is self-evident. Slug is an important EMT inducer, which is related to the development of lung cancer. Cell growth, clone assay, cell migration, cell invasion, and protein expression, and NSCLC transplanted tumor growth were performed in A549, H1299, and H1975 cells. Rosthorin A significantly inhibited the growth of NSCLC cells, it could prolong the survival of nude mice. Rosthorin A inhibited the migration and invasion of A549, H1299, and H1975 cells. Rosthorin A up-regulated E-cadherin expression level and down-regulated the expression of β-catenin, N-cadherin, vimentin, Slug, and Twist. Rosthorin A could promote the expression of E-cadherin and inhibit the development of EMT by downregulating Slug, to inhibit the development and metastasis of NSCLC cells. In summary, Rosthorin A could be used as a promising candidate for the treatment of NSCLC patients with recurrence and metastasis. Show less

Diabetic foot ulcer (DFU), with a high rate of amputation and mortality, is a serious complication of diabetes. However, the therapeutic effect of diabetic foot is poor. This study aimed to investigate the effect of CD147 on epithelial-mesenchymal transition (EMT) process in DFU and molecular mechanisms. Immunohistochemistry was used to reveal the expression of several proteins, such as CD147, E-cadherin, N-cadherin, Slug, and Phospho-RSK2 in DFU, non-diabetic refractory tissues, and wound margin tissues (normal blood glucose). Western blotting was used to analyze the expression of CD147 and Slug in HaCaT cells in the high-glucose environment. HaCaT cells with CD147 or RSK2 knockdown was constructed. Wound healing assay was used to test the migration capability of HaCaT cells with knockdown of CD147. Western blotting was used to detect the protein level of Slug in HaCaT cells with CD147 or RSK2 knockdown to investigate the effects of CD147 or RSK2 on EMT. Immunoprecipitation (IP) assay was used to detect the interaction between CD147 and RSK2. The expression levels of CD147 and Slug in the epithelial cells of marginal DFU tissues were significantly lower than those in non-diabetic refractory tissues and wound margin tissues (all CD147 could cause DFU re-epithelialization obstacle via affecting RSK2-mediated Slug/EMT process, which might be an underlying mechanism for the slow healing of DFU. Show less

Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome pathway. Deubiquitinases (DUBs) can counteract the Snail degradation process to maintain high level of Snail protein in cancer cells. In this study, we screened a cDNA library containing 79 DUBs, and discovered that a panel of DUBs consisting of USP13, USP28, USP29, USP37, OTUD6A, and DUB3 can markedly stabilize Snail protein, with USP29 displaying the strongest activity to prevent Snail degradation. Mechanistically, USP29 enhances the interaction of Snail and SCP1, resulting in simultaneous dephosphorylation and deubiquitination of Snail and thereafter cooperative prevention of Snail degradation. Biologically, ectopic expression of USP29 promotes gastric cancer cell migration, and depletion of Snail abolishes USP29-mediated cell migration; and USP29 can be induced by major EMT and metastatic inducing factors such as TGFβ, TNFα, and hypoxia. More importantly, high expression levels of Snail, USP29, and SCP1 are associated with poor survival and prognosis. Collectively, these data indicate that Snail is a crucial substrate for USP29 to promote cell migration and USP29/SCP1 complex may be new therapeutic targets to treat metastatic cancer. Show less

Breast cancer (BC) is one of the most lethal malignant tumors and the leading cause of cancer-related death worldwide. Although early diagnostic techniques for BC have been well developed, 40% of cases are still diagnosed at the advanced stage, while for BC patients with distant metastases, the 5-year survival rate is usually lower than 30%. The Snail family, generally regarded as transcriptional repressors, has been indicated to be an essential prognostic factor in malignant tumors. However, limited data exist on public databases concerning the prognostic value of individual Snail family members in BC, especially SNAI3. Data from public databases including cBioPortal for Cancer Genomics, Gene Expression Omnibus, UCSC Xena Browser, and Human Protein Atlas (HPA) were downloaded. Based on the Kaplan¬-Meier plotter platform, correlation of the three members of the Snail family and prognosis in BC were analyzed. Individual Snail family members and their co-expressed genes were respectively enriched on different pathways and biological processes via the functional enrichment analysis (FunRich) tool. High SNAI1 mRNA expression was associated with shorter distant metastasis-free survival (DMFS) in all BC patients regardless of PAM50 subtype. Conversely, high SNAI3 mRNA expression was associated with longer DMFS. Although the presence of SNAI2 expression was significantly associated with DMFS in the whole cohort, no significant correlation was found in patients with luminal A or HER2 subtype. For patients with the most diverse clinicopathological features, high SNAI1 expression was associated with poor survival, with the converse being true for SNAI3. However, the impact on prognosis of patients with different clinicopathological features produced by SNAI2 expression was inconclusive. Furthermore, we discovered that SNAI1 or SNAI2 and their co-expressed genes frequently enriched receptor tyrosine kinase (RTK) signaling and integrin-related pathways which mainly functioned on epithelial-mesenchymal transition and were further involved in several processes of signal transduction and cell communication. Furthermore, as SNAI3, along with its co-expressed genes, enriched immune-related pathways, it may thus play a role in mediating the immune system. Our analysis revealed that SNAI1 mRNA expression may potentially be a negative prognostic factor, whereas SNAI3 mRNA was associated with positive prognosis in BC. Therefore, the assessment of SNAI1 and SNAI3 expression may be valuable for predicting prognosis in BC patients. Show less

To investigate the effect of COL8A2 repression on corneal endothelial cells (CECs) in vitro and in vivo. Cultured human CECs (hCECs) were transfected with COL8A2 siRNA (siCOL8A2), and the cell viability and proliferation rate were measured. The expression of cell proliferation-associated molecules was evaluated by Western blotting and real-time reverse transcription PCR. Cell shape, Wingless-INT (WNT) signaling, and mitochondrial oxidative stress were also measured. For in vivo experiments, siCOL8A2 was transfected into rat CECs (rCECs), and corneal opacity and corneal endothelium were evaluated. After transfection with siCOL8A2, COL8A2 expression was reduced (80%). Cell viability, cell proliferation rate, cyclin D1 expression, and the number of cells in the S-phase were reduced in siCOL8A2-treated cells. The cell attained a fibroblast-like shape, and SNAI1, pSMAD2, and β-catenin expression, along with mitochondrial mass and oxidative stress levels, were altered. Corneal opacity increased, and the CECs were changed in rats in the siCOL8A2 group. COL8A2 is required to maintain normal wound healing and CEC function. Show less

RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer tissues and negatively correlated with the survival time of patients. Overexpression of RNF8 promotes the EMT process and migration ability of lung cancer cells, while knockdown of RNF8 demonstrates the opposite effects. In addition, overexpression of RNF8 activates the PI3K/Akt signaling pathway, knockdown of RNF8 by siRNA inhibits this activation, and pharmacologic inhibition of PI3K/Akt in RNF8-overexpressing cells also reduces the expression of EMT markers and the ability of migration. Furthermore, RNF8 is found to directly interact with Slug and promoted the K63-Ub of Slug, and knockdown of Slug disrupts RNF8-dependent EMT in A549 cells, whereas overexpression of Slug rescues RNF8-dependent MET in H1299 cells, and depletion of RNF8 expression by shRNA inhibits metastasis of lung cancer cells Show less

Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell survival, especially in metastatic cancer progression. Epithelial-mesenchymal transition (EMT) plays an important role in metabolic rewiring of cancer cells as well as in phenotypic conversion and therapeutic resistance. Snail (SNAI1), a well-known inducer of cancer EMT, is critical in providing ATP and NADPH via suppression of several gatekeeper genes involving catabolic metabolism, such as phosphofructokinase 1 (PFK1), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase 2 (ACC2). Paradoxically, PFK1 and FBP1 are counter-opposing and rate-limiting reaction enzymes of glycolysis and gluconeogenesis, respectively. In this study, we report a distinct metabolic circuit of catabolic metabolism in breast cancer subtypes. Interestingly, PFKP and FBP1 are inversely correlated in clinical samples, indicating different metabolic subsets of breast cancer. The luminal types of breast cancer consist of the pentose phosphate pathway (PPP) subset by suppression of PFKP while the basal-like subtype (also known as triple negative breast cancer, TNBC) mainly utilizes glycolysis and mitochondrial fatty acid oxidation (FAO) by loss of FBP1 and ACC2. Notably, PPP remains active via upregulation of TIGAR in the FBP1-loss basal-like subset, indicating the importance of PPP in catabolic cancer metabolism. These results indicate different catabolic metabolic circuits and thus therapeutic strategies in breast cancer subsets. Show less