Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF(beta-TrCP) E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF(beta-TrCP) complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF(beta-TrCP) recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.
Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic micro-RNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LCMSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. Conclusion: S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013;57:2274-2286 T he tumor microenvironment plays an important role in modulating cancer and cancer stem cell progression. 1,2 Recently, mesenchymal stem cells (MSCs), as a pivotal part of the tumor stroma, have attracted great attention for their ability to participate in tumor proliferation 3 and metastasis. 4 Although several lines of evidence demonstrate that MSCs can be activated by cancer cells and contribute to tumor progression, the Abbreviations:: cDNA, complementary DNA; ELISA, enzyme-linked immunosorbent assay; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; LCMSCs, liver cancer-associated MSCs; LN-MSCs, liver normal MSCs; miRNA, microRNA; miR-155, microRNA-155; MMP9, matrix metalloproteinases 9; MSCs, mesenchymal stem cells; qRT-PCR, quantitative real time polymerase chain reaction; siRNA, small interfering RNA; SOCS1, suppressor of cytokine signaling 1; STAT, signal transducer and activator of transcription.From the
Emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor-related miRNAs were significantly decreased. Among these miRNAs, miR-125b expression was most strongly suppressed. We also found down-regulation of miR-125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR-125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR-125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR-125b attenuated EMT-associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR-125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR-125b suppressed EMT and EMT-associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR-125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR-125b for liver cancer. Conclusion: miR-125b exerts inhibitory effects on EMT and EMT-associated traits in HCC by SMAD2 and 4. Ectopic expression of miR125b provides a promising strategy to treat HCC. (HEPATOLOGY 2015;62:801-815) H epatocellular carcinoma (HCC) is the fifthmost common cancer in the world and has a high mortality because of a lack of effective treatments. 1 Most HCC patients display symptoms of intrahepatic metastases or postsurgical recurrence with a low survival rate. Emerging evidence suggests that the epithelial-mesenchymal transition (EMT) contributes to tumor metastasis and recurrence, including in liver
Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell's EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway.
Long noncoding RNAs (lncRNAs), a new class of RNAs with no protein-coding potential, have been reported to have crucial roles in the regulation of a variety of tumors. However, the functions and molecular mechanisms of lncRNAs to osteosarcoma are still largely unknown. The purpose of this study is to examine the expression, functions and molecular mechanisms of a new lncRNA FGFR3 antisense transcript 1 (FGFR3-AS1) in osteosarcoma. The expression of FGFR3-AS1 was examined by real-time quantitative PCR. The regulation of FGFR3 by FGFR3-AS1 was examined by RNase protection assay, real-time quantitative PCR, western blotting, and luciferase reporter assay. The effects of FGFR3-AS1 on osteosarcoma cell proliferation and cell cycle were determined by Cell Counting Kit-8, Ethynyl deoxyuridine incorporation assay and flow cytometry. FGFR3-AS1 was upregulated in osteosarcoma. Increased FGFR3-AS1 expression correlates with large tumor size, advanced Enneking stage, metastasis and poor survival. Through antisense pairing with FGFR3 3'UTR, FGFR3-AS1 increases FGFR3 mRNA stability and upregulates FGFR3 expression. The expression of FGFR3-AS1 and FGFR3 is positively correlated in osteosarcoma tissues. Knockdown of FGFR3-AS1 inhibits the proliferation and cell cycle progression of osteosarcoma cells in vitro. Moreover, knockdown of FGFR3-AS1 inhibits xenograft tumor growth of osteosarcoma cells in vivo. These data demonstrate the mechanisms of how antisense noncoding RNA regulate the expression of sense genes, and show the pivotal functions of FGFR3-AS1 in osteosarcoma.
The high incidence rate of hepatocellular carcinoma (HCC) is mainly the result of frequent metastasis and tumor recurrence. Unfortunately, the underlying molecular mechanisms driving HCC metastasis are still not fully understood. It has been demonstrated that tumor stroma cells contribute to primary tumor growth and metastasis. Within the HCC environment, activated hepatic stellate cells (HSCs) can release a number of molecules and enhance cancer cell proliferation and invasiveness in a paracrine manner. Here, for the first time, we demonstrate that epimorphin (EPM; also called syntaxin-2), an extracellular protein, is strongly elevated in activated HSCs within tumor stroma. We show that knockdown of EPM expression in HSCs substantially abolishes their effects on cancer cell invasion and metastasis. Ectopic expression of EPM in HCC cancer cells enhances their invasiveness; we demonstrate that the cells expressing EPM have markedly increased metastasis potential. Furthermore, EPM-mediated invasion and metastasis of cancer cells is found to require up-regulation of matrix metalloproteinase-9 (MMP-9) through the activation of focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) axis. Conclusion: Our results show that EPM, secreted by activated HSCs within HCC stroma, promotes invasion and metastasis of cancer cells by activating MMP-9 expression through the FAK-ERK pathway.
Short-chain fructooligosaccharides (FOS) were supplemented to the diets of nine quarter horses ranging in age from 489 to 539 d with initial BW averaging 400.6 +/- 21.2 kg. The objectives of this study were to determine the effects of dietary FOS on the fecal responses in terms of pH, the microbial population, and VFA concentrations. The horses were used in a 3 x 3 replicated Latin square design, fed according to NRC requirements, and their individual diets were supplemented with no FOS (CON), 8 g of FOS/d (LOW), or 24 g of FOS/d (HIGH) over three 10-d feeding periods. On the last 3 d of each 10-d feeding period, a single fecal sample was collected between 0730 and 0930. Fecal pH decreased linearly (P = 0.01) from 6.48 with the CON diet to 6.38 with the HIGH diet, but there was no change (P = 0.19 for linear effect) in fecal consistency among treatments. A quadratic effect (P < 0.01) was observed for fecal Escherichia coli population, but no difference (P = 0.88 for linear effect) was found in fecal Lactobacilli enumeration among treatments. The presence of fecal Bifidobacteria was unable to be confirmed and was therefore not reported. Fecal acetate concentrations increased linearly (P = 0.03), with means of 2.13, 2.18, and 2.52 mg/g of wet feces for CON, LOW, and HIGH treatments, respectively. Similarly, fecal propionate concentrations increased linearly (P = 0.01), with means of 0.58, 0.64, and 0.73 mg/g for CON, LOW, and HIGH treatments, respectively. Fecal butyrate concentrations also increased linearly (P = 0.02), with means of 0.40, 0.46, and 0.54 mg/g for CON, LOW, and HIGH treatments, respectively. Total VFA (P = 0.01) and lactate (P = 0.02) concentrations increased linearly, with total VFA means of 3.47, 3.69, and 4.25 mg/g for CON, LOW, and HIGH treatments, respectively, and lactate means of 0.36, 0.41, and 0.47 mg/g for CON, LOW, and HIGH treatments, respectively. Supplementing FOS in diets fed to yearling horses altered fecal microbial populations, fecal VFA concentrations, and pH.
The results of this meta-analysis do not support the use of platelet-rich plasma/platelet-rich fibrin matrix in patients with rotator cuff injuries.
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