Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

Background m6A modification has been proved to play an important role in many biological processes. METTL3 as the main methyltransferase for methylation process has been found to be upregulated in many cancers, including CRC. Here, we investigate m6A modification and the underlying mechanism of METTL3 in the development of CRC. Methods The expression of METTL3 was detected in large clinical patient samples. To evaluate the function of METTL3 in vitro and in vivo, colony formation, CCK-8, cell migration and invasion assays were performed. To find out the downstream target of METTL3, GEO dataset was re-mined. We analyzed expression and metastasis-related miRNA by Pearson correlation, and miR-1246 was selected. Here, to identify the downstream target of miR-1246, Targetscan and miRWalk were used. RIP and luciferase reporter assay further confirmed SPRED2 as the direct target of miR-1246. Results We found that upregulated METTL3 is responsible for abnormal m6A modification in CRC and correlates positively with tumor metastasis. The gain- and loss-of-function indicates that METTL3 promotes cell migration and invasion in vitro and in vivo. Additionally, we confirmed that METTL3 can methylate pri-miR-1246, which further promotes the maturation of pri-miR-1246. By using bioinformatics tools, anti-oncogene SPRED2 was identified as the downstream target of miR-1246, wherein downregulated SPRED2 further reverses the inhibition of the MAPK pathway. Conclusions The present study demonstrates that the METTL3/miR-1246/SPRED2 axis plays an important role in tumor metastasis and provides a new m6A modification pattern in CRC development. Electronic supplementary material The online version of this article (10.1186/s13046-019-1408-4) contains supplementary material, which is available to authorized users.

Background/Aims: Long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) play significant roles in the development of tumors, but the functions of specific lncRNAs and lncRNA-related ceRNA networks have not been fully elucidated for colon adenocarcinoma (COAD). In this study, we aimed to clarify the lncRNA-microRNA (miRNA)-mRNA ceRNA network and potential lncRNA biomarkers in COAD. Methods: We extracted data from The Cancer Genome Atlas (TCGA) and identified COAD-specific mRNAs, miRNAs, and lncRNAs. The biological processes in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed for COAD-specific mRNAs. We then constructed a ceRNA network of COAD-specific mRNAs, miRNAs and lncRNAs and analyzed the correlation between expression patterns and clinical features of the lncRNAs involved. After identifying potential mRNA targets of 4 lncRNAs related to overall survival (OS), we conducted stepwise analysis of these targets through GO and KEGG. Using tissue samples from our own patients, we also verified certain analytical results using quantitative real-time PCR (qRT-PCR). Results: Data from 521 samples (480 tumor tissue and 41 adjacent non-tumor tissue samples) were extracted from TCGA. A total of 258 specific lncRNAs, 206 specific miRNAs, and 1467 specific mRNAs were identified (absolute log₂ [fold change] > 2, false discovery rate < 0.01). Analysis of KEGG revealed that specific mRNAs were enriched in cancer-related pathways. The ceRNA network was constructed with 64 lncRNAs, 18 miRNAs, and 42 mRNAs. Among these lncRNAs involved in the network, 3 lncRNAs (LINC00355, HULC, and IGF2-AS) were confirmed to be associated with certain clinical features and 4 lncRNAs (HOTAIR, LINC00355, KCNQ1OT1, and TSSC1-IT1) were found to be negatively linked to OS (log-rank p < 0.05). KEGG showed that the potential mRNA targets of these 4 lncRNAs may be concentrated in the MAPK pathway. Certain results were validated by qRT-PCR. Conclusion: This study providing novel insights into the lncRNA-miRNA-mRNA ceRNA network and reveals potential lncRNA biomarkers in COAD.

Tubulointerstitial fibrosis (TIF) is the final common pathway in the end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is considered a major contributor to the TIF by increasing the number of myofibroblasts. Curcumin, a polyphenolic compound derived from rhizomes of Curcuma, has been shown to possess potent anti-fibrotic properties but the mechanism remains elusive. We found that curcumin inhibited the EMT as assessed by reduced expression of α-SMA and PAI-1, and increased E-cadherin in TGF-β1 treated proximal tubular epithelial cell HK-2 cells. Both of the conventional TGF-β1/Smad pathway and non-Smad pathway were investigated. Curcumin reduced TGF-β receptor type I (TβR-I) and TGF-β receptor type II (TβR II), but had no effect on phosphorylation of Smad2 and Smad3. On the other hand, in non-Smad pathway curcumin reduced TGF-β1-induced ERK phosphorylation and PPARγ phosphorylation, and promoted nuclear translocation of PPARγ. Further, the effect of curcumin on α-SMA, PAI-1, E-cadherin, TβR I and TβR II were reversed by ERK inhibitor U0126 or PPARγ inhibitor BADGE, or PPARγ shRNA. Blocking PPARγ signaling pathway by inhibitor BADGE or shRNA had no effect on the phosphorylation of ERK whereas the suppression of ERK signaling pathway inhibited the phosphorylation of PPARγ. We conclude that curcumin counteracted TGF-β1-induced EMT in renal tubular epithelial cells via ERK-dependent and then PPARγ-dependent pathway.

MiR-1258 may function as a suppressive factor by negatively controlling E2F8, thus, highlighting the potential role of miR-1258 as a therapeutic target for human CRC.

Aberrant endoplasmic reticulum (ER) stress and autophagy are associated with diabetic nephropathy. Here we investigated the effect of astragaloside IV (AS-IV) on the progression of diabetic nephropathy (DN) and the underlying mechanism involving ER stress and autophagy in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-incubated podocytes. The diabetic mice developed progressive albuminuria and glomerulosclerosis within 8 weeks, which were significantly ameliorated by AS-IV treatment in a dose-dependent manner. Moreover, diabetes or HG-induced podocyte apoptosis was markedly attenuated by AS-IV, paralleled by a marked remission in ER stress and a remarkable restoration in impaired autophagy, which were associated with a significant improvement in the expression of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) and AMP-activated protein kinase α (AMPKα) phosphorylation, respectively. Knockdown of SERCA2 in podocytes induced ER stress and largely abolished the protective effect of AS-IV, but had no obvious effect on the expression of autophagy-associated proteins. On the other hand, blockade of either autophagy induction or AMPKα activation could also significantly mitigate AS-IV-induced beneficial effect. Collectively, these results suggest that AS-IV prevented the progression of DN, which is mediated at least in part by SERCA2-dependent ER stress attenuation and AMPKα-promoted autophagy induction.

BACKGROUND:The GATA3 gene (GATA-binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations. METHODS: The authors examined the somatic mutation status of GATA3 and performed survival analysis in The Cancer Genome Atlas (TCGA) cohort (n 5 934) and the Fudan University Shanghai Cancer Center (FUSCC) cohort (n 5 308). Patient characteristics, including age; menopausal status; tumor laterality; tumor size; lymph node status; tumor grade; molecular subtypes; adjuvant radiotherapy, chemotherapy, and endocrine therapy; and prognosis, together with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and TP53 (tumor protein p53) mutation status, were collected. RESULTS: GATA3 mutations were detected in 8.8% of patients (82 of 934 patients) in the TCGA cohort and 14.9% of patients (46 of 308 patients) in the FUSCC cohort. GATA3 mutations were found to be significantly associated with luminal-like breast cancer (P 5.002 in the TCGA cohort and P <.001 in the FUSCC cohort), and were highly mutually exclusive to PIK3CA mutations (P 5.001 in the TCGA cohort and P 5.003 in the FUSCC cohort) and TP53 mutations (P <.001 in both cohorts). Furthermore, GATA3 mutations were correlated with improved overall survival in the entire population (P 5.025 in the TCGA cohort and P 5.043 in the FUSCC cohort) as well as in patients with luminal-like disease who received adjuvant endocrine therapy. CONCLUSIONS: GATA3 mutations mainly occur in patients with luminal-like breast cancer and have identifiable clinicopathologic and genetic characteristics, highlighting a subgroup of patients with breast cancer in whom limited therapy may be appropriate.

Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded and/or unfolded proteins in ER membranes, is involved in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the role of ER stress inhibitors ursodeoxycholic acid (UDCA) and 4-phenylbutyrate (4-PBA) in the treatment of DN in db/db mice. Findings have revealed that diabetic db/db mice were more hyperglycemic than their non-diabetic controls, and exhibited a marked increase in body weight, water intake, urine volume, fasting plasma glucose, systolic blood pressure, glucose and insulin tolerance. UDCA (40 mg/kg/day) or 4-PBA (100 mg/kg/day) treatment for 12 weeks resulted in an improvement in these biochemical and physical parameters. Moreover, UDCA or 4-PBA intervention markedly decreased urinary albuminuria and attenuated mesangial expansion in diabetic db/db mice, compared with db/db mice treated with vehicle. These beneficial effects of UDCA or 4-PBA on DN were associated with the inhibition of ER stress, as evidenced by the decreased expression of BiP, phospho-IRE1α, phospho-eIF2α, CHOP, ATF-6 and spliced X-box binding protein-1 in vitro and in vivo. UDCA or 4-PBA prevented hyperglycemia-induced or high glucose (HG)-induced apoptosis in podocytes in vivo and in vitro via the inhibition of caspase-3 and caspase-12 activation. Autophagy deficiency was also seen in glomeruli in diabetic mice and HG-incubated podocytes, exhibiting decreased expression of LC3B and Beclin-1, which could be restored by UDCA or 4-PBA treatment. Taken together, our results have revealed an important role of ER stress in the development of DN, and UDCA or 4-PBA treatment may be a potential novel therapeutic approach for the treatment of DN.