Identification of a novel GSK3ß inhibitor involved in abrogating KRas dependent pancreatic tumors in Wnt/beta-catenin and NF-kB dependent manner.

Pancreatic cancer is an aggressive malignancy with a poor survival rate because it is difficult to diagnose the disease during its early stages. The currently available treatments, which include surgery, chemotherapy and radiation therapy, offer only limited survival benefit. Pharmacological interventions to inhibit Glycogen Synthase Kinase-3beta (GSK3ß) activity is an important therapeutic strategy for the treatment of pancreatic cancer because GSK3ß is one of the key factors involved in the onset, progression as well as in the acquisition of chemoresistance in pancreatic cancer. Here, we report the identification of MJ34 as a potent GSK3ß inhibitor that significantly reduced growth and survival of human mutant KRas dependent pancreatic tumors. MJ34 mediated GSK3ß inhibition was seen to induce apoptosis in a ß-catenin dependent manner and downregulate NF-kB activity in MiaPaCa-2 cells thereby impeding cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic cancer. In vivo acute toxicity and in vitro cardiotoxicity studies indicate that MJ34 is well tolerated without any adverse effects. Taken together, we report the discovery of MJ34 as a potential drug candidate for the therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3ß.

Inhibition of Wnt/ß-catenin signaling by monensin in cervical cancer.

The challenging clinical outcomes associated with advanced cervical cancer underscore the need for a novel therapeutic approach. Monensin, a polyether antibiotic, has recently emerged as a promising candidate with anti-cancer properties. In line with these ongoing efforts, our study presents compelling evidence of monensin's potent efficacy in cervical cancer. Monensin exerts a pronounced inhibitory impact on proliferation and anchorage-independent growth. Additionally, monensin significantly inhibited cervical cancer growth in vivo without causing any discernible toxicity in mice. Mechanism studies show that monensin's anti-cervical cancer activity can be attributed to its capacity to inhibit the Wnt/ß-catenin pathway, rather than inducing oxidative stress. Monensin effectively reduces both the levels and activity of ß-catenin, and we identify Akt, rather than CK1, as the key player involved in monensin-mediated Wnt/ß-catenin inhibition. Rescue studies using Wnt activator and ß-catenin-overexpressing cells confirmed that ß-catenin inhibition is the mechanism of monensin's action. As expected, cervical cancer cells exhibiting heightened Wnt/ß-catenin activity display increased sensitivity to monensin treatment. In conclusion, our findings provide pre-clinical evidence that supports further exploration of monensin's potential for repurposing in cervical cancer therapy, particularly for patients exhibiting aberrant Wnt/ß-catenin activation.

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most aggressive subtype of kidney tumour with a poor prognosis and an increasing incidence rate worldwide. Brusatol, an essential active ingredient derived from Brucea javanica, exhibits potent antitumour properties. Our study aims to explore a novel treatment strategy for RCC patients. We predicted 37 molecular targets of brusatol based on the structure of brusatol, and MEF2A (Myocyte Enhancer Factor 2A) was selected as our object through bioinformatic analyses. We employed various experimental techniques, including RT-PCR, western blot, CCK8, colony formation, immunofluorescence, wound healing, flow cytometry, Transwell assays and xenograft mouse models, to investigate the impact of MEF2A on RCC. MEF2A expression was found to be reduced in patients with RCC, indicating a close correlation with MEF2A deubiquitylation. Additionally, the protective effects of brusatol on MEF2A were observed. The overexpression of MEF2A inhibits RCC cell proliferation, invasion and migration. In xenograft mice, MEF2A overexpression in RCC cells led to reduced tumour size compared to the control group. The underlying mechanism involves the inhibition of RCC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) through the modulation of Wnt/ß-catenin signalling. Altogether, we found that MEF2A overexpression inhibits RCC progression by Wnt/ß-catenin signalling, providing novel insight into diagnosis, treatment and prognosis for RCC patients.

miR-1-3p Inhibits Osteosarcoma Cell Proliferation and Cell Cycle Progression While Promoting Cell Apoptosis by Targeting CDK14 to Inactivate Wnt/Beta-Catenin Signaling.

Osteosarcoma (OS) is a common bone malignancy and is diagnosed frequently in children and young adults. According to previous RNA sequencing, miR-1-3p is downregulated in OS clinical samples. Nevertheless, the functions of miR-1-3p in OS cell process and the related mechanism have not been revealed yet. In the current study, miR-1-3p expression in OS tissues and cells were evaluated using quantitative polymerase chain reaction. CCK-8 assays were conducted to measure OS cell viability in response to miR-1-3p overexpression. Colony forming assays and EdU staining were conducted for measurement of cell proliferation, and flow cytometry analysis was performed to determine cell apoptosis and cell cycle progression. Protein levels of apoptotic markers, beta-catenin, and Wnt downstream targets were quantified using western blotting. The binding relation between miR-1-3p and cyclin dependent kinase 14 (CDK14) was validated utilizing luciferase reporter assays. Experimental results revealed that miR-1-3p expression was decreased in OS tissues and cells. Additionally, miR-1-3p inhibited cell proliferation and cell cycle progression while enhancing OS cell apoptosis. Moreover, miR-1-3p directly targeted CDK14 and inversely regulated CDK14 expression in OS cells. Furthermore, miR-1-3p inactivated the Wnt/beta-catenin signaling. CDK14 overexpression partially rescued the inhibitory impact of miR-1-3p on OS cell growth. Overall, miR-1-3p inhibits OS cell proliferation and cell cycle progression while promoting cell apoptosis by targeting CDK14 and inactivating the Wnt/beta-catenin signaling.

Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms.

Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/ß-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

MFG-E8 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells through GSK3ß/ß-catenin signaling pathway.

Fracture nonunion and bone defects are challenging for orthopedic surgeons. Milk fat globule-epidermal growth factor 8 (MFG-E8), a glycoprotein possibly secreted by macrophages in a fracture hematoma, participates in bone development. However, the role of MFG-E8 in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is unclear. We investigated the osteogenic effect of MFG-E8 in vitro and in vivo. The CCK-8 assay was used to assess the effect of recombinant human MFG-E8 (rhMFG-E8) on the viability of hBMSCs. Osteogenesis was investigated using RT-PCR, Western blotting, and immunofluorescence. Alkaline phosphatase (ALP) and Alizarin red staining were used to evaluate ALP activity and mineralization, respectively. An enzyme-linked immunosorbent assay was conducted to evaluate the secretory MFG-E8 concentration. Knockdown and overexpression of MFG-E8 in hBMSCs were established via siRNA and lentivirus vector transfection, respectively. Exogenous rhMFG-E8 was used to verify the in vivo therapeutic effect in a tibia bone defect model based on radiographic analysis and histological evaluation. Endogenous and secretory MFG-E8 levels increased significantly during the early osteogenic differentiation of hBMSCs. Knockdown of MFG-E8 inhibited the osteogenic differentiation of hBMSCs. Overexpression of MFG-E8 and rhMFG-E8 protein increased the expression of osteogenesis-related genes and proteins and enhanced calcium deposition. The active ß-catenin to total ß-catenin ratio and the p-GSK3ß protein level were increased by MFG-E8. The MFG-E8-induced enhanced osteogenic differentiation of hBMSCs was partially attenuated by a GSK3ß/ß-catenin signaling inhibitor. Recombinant MFG-E8 accelerated bone healing in a rat tibial-defect model. In conclusion, MFG-E8 promotes the osteogenic differentiation of hBMSCs by regulating the GSK3ß/ß-catenin signaling pathway and so, is a potential therapeutic target.

The roles of protocadherin-7 in colorectal cancer cells on cell proliferation and its chemoresistance.

Despite the high mutation frequencies of KRAS, NRAS, and BRAF in colorectal cancer (CRC), there are no effective and reliable inhibitors for these biomarkers. Protocadherin-7 (PCDH7) is regarded as a potentially targetable surface molecule in cancer cells and plays an important role in their proliferation, metastasis, and drug resistance. However, the roles and underlying mechanisms of PCDH7 in CRC remain unclear. In the current study, we found that different colorectal cancer cells expressed PCDH7 over a wide range. The levels of PCDH7 expression were positively associated with cell proliferation and drug resistance in CRC cells but negatively correlated with the potential for cell migration and invasion. Our data indicated that PCDH7 mediated the resistance of CRC cells to ABT-263 (a small-molecule Bcl-2 inhibitor that induces apoptosis) by inhibiting cell apoptosis, which was supported by the downregulation of caspase-3, caspase-9, and PARP cleavage. We found that PCDH7 effectively promoted Mcl-1 expression at both mRNA and protein levels. Furthermore, PCDH7 activated the Wnt signaling pathway, which was confirmed by the increase in ß-catenin and c-Myc expression. Finally, and notably, S63845, a novel Mcl-1 inhibitor, not only effectively attenuated the inhibitory effect of PCDH7 on cell apoptosis induced by ABT-263 in vitro but also sensitized PCDH7-overexpressed CRC cell-derived xenografts to ABT-263 in vivo. Taken together, although PCDH7 inhibited the migration and invasion of CRC cells, it could facilitate the development of drug resistance in colorectal cancer cells by positively modulating Mcl-1 expression. The application of the Mcl-1 inhibitor S63845 could be a potential strategy for CRC chemotherapy, especially in CRC with high levels of PCDH7.

Long non-coding RNA SNHG11 regulates the Wnt/ß-catenin signaling pathway through rho/ROCK in trabecular meshwork cells.

Trabecular meshwork (TM) cell dysfunction is the leading cause of elevated intraocular pressure (IOP) and glaucoma. The long non-coding RNA (lncRNA) small nucleolar RNA host gene 11 (SNHG11) is associated with cell proliferation and apoptosis, but its biological functions and role in glaucoma pathogenesis remain unclear. In the present study, we investigated the role of SNHG11 in TM cells using immortalized human TM and glaucomatous human TM (GTM3 ) cells and an acute ocular hypertension mouse model. SNHG11 expression was depleted using siRNA targeting SNHG11. Transwell assays, quantitative real-time PCR analysis (qRT-PCR), western blotting, and CCK-8 assay were used to evaluate cell migration, apoptosis, autophagy, and proliferation. Wnt/ß-catenin pathway activity was inferred from qRT-PCR, western blotting, immunofluorescence, and luciferase reporter and TOPFlash reporter assays. The expression of Rho kinases (ROCKs) was detected using qRT-PCR and western blotting. SNHG11 was downregulated in GTM3 cells and mice with acute ocular hypertension. In TM cells, SNHG11 knockdown inhibited cell proliferation and migration, activated autophagy, and apoptosis, repressing the Wnt/ß-catenin signaling pathway, and activated Rho/ROCK. Wnt/ß-catenin signaling pathway activity increased in TM cells treated with ROCK inhibitor. SNHG11 regulated Wnt/ß-catenin signaling through Rho/ROCK by increasing GSK-3ß expression and ß-catenin phosphorylation at Ser33/37/Thr41 while decreasing ß-catenin phosphorylation at Ser675. We demonstrate that the lncRNA SNHG11 regulates Wnt/ß-catenin signaling through Rho/ROCK via ß-catenin phosphorylation at Ser675 or GSK-3ß-mediated phosphorylation at Ser33/37/Thr41, affecting cell proliferation, migration, apoptosis, and autophagy. Through its effects on Wnt/ß-catenin signaling, SNHG11 is implicated in glaucoma pathogenesis and is a potential therapeutic target.

Comparison of the Cost and Effect of Combined Conditioned Medium and Conventional Medium for Fallopian Tube Organoid Cultures.

Fallopian tube epithelial cells (FTEC) are thought to be the cell of origin of high-grade serous ovarian carcinoma. FTEC organoids can be used as research models for the disease. Nevertheless, culturing organoids requires a medium supplemented with several expensive growth factors. We proposed that a combined conditioned medium based on the composition of the fallopian tubes, including epithelial, stromal, and endothelial cells could enhance FTEC organoid formation. We derived two primary culture cell lines from the fimbria portion of the fallopian tubes. The organoids were split into conventional or combined medium groups based on what medium they were grown in and compared. The number and size of the organoids were evaluated. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were used to evaluate gene and protein expression (PAX8, FOXJ1, beta-catenin, and stemness genes). Enzyme-linked immunosorbent assay was used to measure Wnt3a and RSPO1 in both mediums. DKK1 and LiCl were added to the mediums to evaluate their influence on beta-catenin signaling. The growth factor in the combined medium was evaluated by the growth factor array. We found that the conventional medium was better for organoids regarding proliferation (number and size). In addition, WNT3A and RSPO1 concentrations were too low in the combined medium and needed to be added making the cost equivalent to the conventional medium. However, the organoid formation rate was 100% in both groups. Furthermore, the combined medium group had higher PAX8 and stemness gene expression (OLFM4, SSEA4, LGR5, B3GALT5) when compared with the conventional medium group. Wnt signaling was evident in the organoids grown in the conventional medium but not in the combined medium. PLGF, IGFBP6, VEGF, bFGF, and SCFR were found to be enriched in the combined medium. In conclusion, the combined medium could successfully culture organoids and enhance PAX8 and stemness gene expression. However, the conventional medium was a better medium for organoid proliferation. The expense of both mediums was comparable. The benefit of using a combined medium requires further exploration.

Adipose mesenchymal stem cells-derived exosomes alleviate osteoarthritis by transporting microRNA -376c-3p and targeting the WNT-beta-catenin signaling axis.

Osteoarthritis (OA), one of the major diseases afflicting the elderly, is a type of degenerative joint disease related to cartilage and synovium. This study aimed to clarify the role and mechanism of adipose mesenchymal stem cell (ADSC)-derived exosomes (Exos) in OA-induced chondrocyte degradation and synovial hyperplasia, thus improving the quality of life of patients. The rat OA model, chondrocytes, synovial fibroblast models and immunofluorescence were applied to observe the in vivo and in vitro functions of human ADSC (hADSC)-derived Exos in OA and its possible regulatory signaling pathways. Bioinformatics software and luciferase reporter assay were carried out to verify the mechanism of microRNA-376c-3p (miR-376c-3p) in hADSC-derived Exos in OA in vitro. Moreover, Safranine O-Fast Green Cartilage staining, Masson staining, immunohistochemistry and immunofluorescence were conducted to verify the role of miR-376c-3p in hADSC-derived Exos in OA in vivo. hADSC-derived Exos mitigated OA-induced chondrocyte degradation and synovial fibrosis both in vivo and in vitro models by repressing the WNT-beta-catenin signaling pathway. For the mechanism exploration in vitro, miR-376c-3p was raised in hADSC-derived Exos and mediated the fibrosis of synovial fibroblasts in OA, and miR-376c-3p targeted the 3'-untranslated region of WNT3 or WNT9a. Meanwhile, the in vivo experiments also corroborated that the miR-376c-3p in hADSC-derived Exos mitigated OA-induced chondrocyte degradation and synovial fibrosis. MiR-376c-3p in hADSC-derived Exos repressed the WNT-beta-catenin pathway by targeting WNT3 or WNT9a, and then mitigating OA-induced chondrocyte degradation and synovial fibrosis, thereby providing theoretical basis for clinical implementation of treatment.

Interplay between lncRNA/miRNA and Wnt/ß-catenin signaling in brain cancer tumorigenesis.

Brain cancers are among the most aggressive malignancies with high mortality and morbidity worldwide. The pathogenesis of brain cancers is a very complicated process involving various genetic mutations affecting several oncogenic signaling pathways like Wnt/ß-catenin axis. Uncontrolled activation of this oncogenic signaling is associated with decreased survival rate and poor prognosis in cancer patients. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) were shown to play important roles in regulating cell proliferation, differentiation, and apoptosis by regulating the expression of their target genes. Aberrant expression of these non-coding RNAs (ncRNAs) was reported in many human cancers, including glioblastoma, medulloblastoma, meningioma, and pituitary adenoma. Multiple lncRNAs were shown to participate in brain tumor pathogenesis by targeting Wnt signaling regulatory miRNAs. SNHG7/miR-5095, PCAT6/miR-139-3p, SNHG6/miR-944, SNHG1/ miR-556-5p, SNHG17/ miR-506-3p, LINC00702/miR-4652-3p, DLGAP1-AS1/miR-515-5p, HOTAIR/miR-1, HOTAIR/miR-206, CRNDE/miR-29c-3p, AGAP2-AS1/ miR-15a/b-5p, CLRN1-AS1/miR-217, MEG3/miR-23b-3p, and GAS5/miR-27a-5p are identified lncRNA/miRNA pairs that are involved in this process. Therefore, recognition of the expression profile and regulatory role of ncRNAs on the Wnt signaling may offer a novel approach to the diagnosis, prognosis, and treatment of human cancers. This review summarizes previous data on the modulatory role of lncRNAs/miRNAs on the Wnt/ß-catenin pathway implicated in tumor growth, EMT, metastasis, and chemoresistance in brain cancers.

Wnt/ß-catenin signaling pathway in the tumor progression of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/ß-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/ß-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/ß-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/ß-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/ß-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.

The interplay between non-coding RNAs and Wnt/ß-catenin signaling pathway in urinary tract cancers: from tumorigenesis to metastasis.

Non-coding RNAs (ncRNAs) are emerging as important regulators in various pathological conditions including tumorigenesis, metastasis, and drug resistance in human cancers. Oncogenic or tumor suppressor ncRNAs exert prominent effects on cell proliferation, migration and invasion in cancer cells through modulating various signaling pathways including Wnt/ß-catenin. Upregulation of the oncogenic Wnt/ß-catenin pathway was reported to be implicated in multiple human cancers including breast, liver, colorectal, and urothelial cancers. Therefore, identifying interactions between ncRNAs and canonical Wnt signaling components may represent novel therapeutic targets for better treatment and management of cancer. In this review, we summarized the recent findings about miRNA/lncRNA-dependent mechanisms that regulate Wnt/ß-catenin signaling involved in tumorigenesis and metastasis of urinary tract cancers.

MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy.

BACKGROUND: The active metabolite of 5-Fluorouracil (5FU), used in the treatment of several types of cancer, acts by inhibiting the thymidylate synthase encoded by the TYMS gene, which catalyzes the rate-limiting step in DNA replication. The major failure of 5FU-based cancer therapy is the development of drug resistance. High levels of TYMS-encoded protein in cancerous tissues are predictive of poor response to 5FU treatment. Expression of TYMS is regulated by various mechanisms, including involving non-coding RNAs, both miRNAs and long non-coding RNAs (lncRNAs). AIM: To delineate the miRNAs and lncRNAs network regulating the level of TYMS-encoded protein. MAIN BODY: Several miRNAs targeting TYMS mRNA have been identified in colon cancers, the levels of which can be regulated to varying degrees by lncRNAs. Due to their regulation by the MALAT1 lncRNA, these miRNAs can be divided into three groups: (1) miR-197-3p, miR-203a-3p, miR-375-3p which are downregulated by MALAT1 as confirmed experimentally and the levels of these miRNAs are actually reduced in colon and gastric cancers; (2) miR-140-3p, miR-330-3p that could potentially interact with MALAT1, but not yet supported by experimental results; (3) miR-192-5p, miR-215-5p whose seed sequences do not recognize complementary response elements within MALAT1. Considering the putative MALAT1-miRNAs interaction network, attention is drawn to the potential positive feedback loop causing increased expression of MALAT1 in colon cancer and hepatocellular carcinoma, where YAP1 acts as a transcriptional co-factor which, by binding to the TCF4 transcription factor/ ß-catenin complex, may increase the activation of the MALAT1 gene whereas the MALAT1 lncRNA can inhibit miR-375-3p which in turn targets YAP1 mRNA. CONCLUSION: The network of non-coding RNAs may reduce the sensitivity of cancer cells to 5FU treatment by upregulating the level of thymidylate synthase.

Loss of HOXA10 causes endometrial hyperplasia progressing to endometrial cancer.

Endometrial cancer is the fourth most common malignancy in women and the precursor lesion is endometrial hyperplasia. HOXA10 is a transcription factor that plays key roles in endometrial functions such as the endowment of receptivity, embryo implantation, and trophoblast invasion. Herein, using testicular transgenesis, we developed transgenic mice that expressed a shRNA against HOXA10 and there was a nearly 70% reduction in the expression of HOXA10 in these animals. We observed that downregulation of HOXA10 led to the development of endometrial hyperplasia in the young animals (3 months), and as they aged (>1 year), most animals developed well-differentiated endometrial adenocarcinoma. In the endometrium of animals with reduced HOXA10, there was increased proliferation and elevated levels of ERα and ERß. In parallel, there was increased expression of Wnt4 and ß-Catenin, SOX9, and YAP1. We propose that chronic reduction in HOXA10 expression disrupts multiple pathways in the uterus that aids in the development of endometrial hyperplasia which progresses to endometrial cancer with age.

The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells.

JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, ß-catenin, ß-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, ß-catenin, ß-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.

The NOP14 nucleolar protein suppresses the function and stemness of melanoma stem-like cells through Wnt/beta-catenin signaling inactivation.

Cancer stem cells (CSCs) are closely related to tumor occurrence, development, metastasis, drug resistance, and recurrence. The role of CSCs in melanoma is poorly understood. Our previous studies suggested that the NOP14 nucleolar protein (NOP14) is involved in melanoma pathogenesis regulation. Importantly, NOP14 overexpression inhibits the Wnt/beta (ß)-catenin signaling pathway, an important mechanism regulating CSCs stemness. Therefore, in this study, we aimed to explore the role of NOP14 in the stemness and function of CSCs in melanoma in vitro. CD133, a stem cell marker, was used to identify melanoma stem-like cells (SLCs). NOP14 overexpression subsequently decreased the proportion of CD133+ SLCs, impaired the colony-forming capabilities, and downregulated the expression of Nanog, SOX2, and OCT4 stem cell markers in A375 and A875 cells, suggesting that NOP14 suppresses the stemness of melanoma SLCs. NOP14 overexpression suppressed the migration, invasion, and angiogenesis-inducing ability of A375-SLCs and A875-SLCs. NOP14 overexpression also inactivated Wnt/ß-catenin signaling in melanoma CD133+ SLCs. The Wnt signaling activator BML-284 alleviated the effect of NOP14 overexpression on the stemness and function of melanoma CSCs. In conclusion, NOP14 suppresses the stemness and function of melanoma SLCs by inactivating Wnt/ß-catenin signaling. Thus, NOP14 is a novel target for CSC treatment in melanoma.Abbreviations: CSCs, cancer stem cells; SLCs, stem-like cells; NOP14, NOP14 nucleolar protein; SCID, severe combined immunodeficiency; ß-catenin, beta-catenin; lv-NOP14, lentivirals expressing NOP14; PBS, phosphate buffer saline; HUVECs, human umbilical vein endothelial cells.

The Biological Relevance of NHERF1 Protein in Gynecological Tumors.

Gynecological cancer management remains challenging and a better understanding of molecular mechanisms that lead to carcinogenesis and development of these diseases is needed to improve the therapeutic approaches. The Na+/H+ exchanger regulatory factor 1 (NHERF1) is a scaffold protein that contains modular protein-interaction domains able to interact with molecules with an impact on carcinogenesis and cancer progression. During recent years, its involvement in gynecological cancers has been explored, suggesting that NHERF1 could be a potential biomarker for the development of new targeted therapies suitable to the management of these tumors. This comprehensive review provides an update on the recent study on NHERF1 activity and its pathological role in cervical and ovarian cancer, as well as on its probable involvement in the therapeutic landscape of these cancer types.

The Effects of Exercise and Activity-Based Physical Therapy on Bone after Spinal Cord Injury.

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.