LASP-1 is an actin-binding protein that regulates cytoskeletal dynamics and cell migration. LASP-1 was previously identified in a cDNA library from metastatic breast cancer samples. This protein has since been detected in multiple human cancers, including liver cancer, gastric cancer and pancreatic cancer. S100P is a small calcium-binding protein in the S100 protein family that regulates cellular, physiological and pathological processes in various cancers. However, the clinical significance of LASP-1 and S100P expression in gallbladder cancer (GBC) is not yet clear. In our study, we focused on the clinical significance, biological function and mechanism of LASP-1 in gallbladder cancer and detected LASP-1 and S100P overexpression in GBC tissues. The expression of LASP-1 was significantly correlated with poor prognosis in GBC patients (P < 0.05). Furthermore, down-regulation of LASP-1 expression resulted in the obvious inhibition of proliferation and migration and caused cell cycle arrest by down-regulating S100P via the PI3K/AKT pathway; in mice, tumor volume was significantly decreased. In conclusion, LASP-1 may act as an oncogene to regulate the expression of S100P to influence cellular functions in GBC. LASP-1 could serve as a genetic treatment target in GBC patients.

Worldwide, human pancreatic cancer is a rare malignancy with a poor prognosis. Long non-coding RNAs (lncRNAs) are known to have a crucial role in cancer occurrence and progression; however, the role of pseudogene-expressed lncRNAs, a major type of lncRNA, have not been thoroughly analyzed in cancer. Therefore, the present study focused on zinc finger protein 91 pseudogene (ZFP91-P). ZFP91-P expression was initially detected in two pancreatic cancer cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the highest expression of ZFP91-P was found in the BXPC-3-H cell line. Subsequently, BXPC-3-H cells were transfected with ZFP91-P short hairpin RNA (shRNA) using a plasmid vector and termed shZFP91-P. Cells transfected with negative control plasmid vector were termed shCon. MTT and Transwell assays were performed to analyze the proliferation and migration of BXPC-3-H cells, respectively, and western blotting was used to detect epithelial-mesenchymal transition markers, including vimentin and β-catenin. The present study showed that depletion of ZFP91-P markedly decreased pancreatic cancer cell proliferation and inhibited cell migration capacity. In addition, the expression of β-catenin increased while vimentin expression decreased. The current findings suggest that high expression of ZFP91-P promotes the migration of BXPC-3-H cells and may be a novel marker for early diagnosis for pancreatic cancer.

Chromatin accessibility is critical for tumor development, whose mechanisms remain unclear. As a crucial regulator for chromatin remodeling, BRD4 promotes tumor progression by regulating multiple genes. As a small-molecule inhibitor of BRD4, JQ1 has potent chemotherapeutic activity against various human cancers. However, whether JQ1 has potential anti-tumor effects and how JQ1 regulates global transcription in gastric cancer (GC) remain largely unknown. In this research, we found BRD4 was highly expressed in GC tissues and was significantly associated with poor prognosis. JQ1 inhibited the proliferation and induced apoptosis of GC cells in vitro. Besides, JQ1 suppressed the migration and invasion of cancer cells by inducing MET. Notably, an assay for transposase-accessible chromatin using sequencing (ATAC-seq) data showed that JQ1 obviously downregulated the chromatin accessibility of GC cells and differentially accessible regions were highly enriched for RUNX2-binding motifs. Combinational analysis of ATAC-seq and RNA-seq data discovered NID1 as the downstream target of JQ1 and JQ1 reduced NID1 expression in GC cells. Chromatin immunoprecipitation, luciferase reporter gene assay, and rescue experiments all confirmed that RUNX2/NID1 axis was responsible for JQ1-inhibiting metastasis of GC cells. What's more, high expression of NID1 in GC tissues also predicted poor survival outcome of cancer patients and NID1 knockdown prohibited migration and invasion of cancer cells via partially inducing MET. Finally, in vivo models showed that JQ1 prevented GC growth and suppressed cancer metastasis. In conclusion, JQ1 inhibits the malignant progression of GC by downregulating chromatin accessibility and inactivating RUNX2/NID1 signaling. In addition, NID1 is also a novel therapeutic target for progressive GC patients.

In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01-1.0 μg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor-supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion.

Estrogen-related receptor-α (ERRα) is a nuclear receptor of transcription factor that binds to estrogen responsive elements and estrogen-related responsive elements. Estrogen-related receptor-α is involved in metabolic processes and implicated in the progression and growth of several human malignancies. However, the biologic role and clinical significance of ERRα in gallbladder cancer (GBC) remains to be clarified. Here, we reported that ERRα protein expression was notably higher in GBC tissues than in cholecystitis tissues, and that the aberrantly higher ERRα expression was positively correlated with advanced TNM stage and indicated dismal prognosis of GBC (P < .01). In GBC cell lines NOZ and OCUG, the targeted depletion of ERRα retarded the growth and suppressed the migration and invasive capabilities of GBC cells, and inhibited epithelial-mesenchymal transition by decreasing the expression of mesenchymal markers and elevating the expression of epithelial markers. Moreover, ERRα knockdown inhibited tumor growth in nude mice and led to decreased expression levels of Nectin-4, p-PI3K p85α, and p-AKT. Overexpression of ERRα in the GBC-SD cell line showed exactly the opposite effect. The targeted inhibition of Nectin-4 antagonized GBC cell proliferation and invasion, which were induced by ERRα upregulation. Moreover, Nectin-4 depletion inhibited the ERRα-induced activation of the PI3K/AKT pathway. Chromatin immunoprecipitation analysis and dual-luciferase reporter gene assays showed that ERRα enhanced the transcription of Nectin-4 by binding to the promoter of Nectin-4. In conclusion, our data indicated that ERRα could be a potential target for the genetic treatment of GBC.

Gallbladder cancer (GBC) is one of the mostly aggressive diseases with poor prognosis due to the lack of severe symptoms. To date, little is known about the potential roles and underlying mechanisms of long noncoding RNAs (lncRNAs) in GBC initiation and progression. Thus, it provides us with a novel insight into the contribution of lncRNAs to GBC development. Remarkably, we found the differential expression of a lncRNA, namely, KIAA0125, in a pair of GBC cell sublines which possess different metastatic potentials. Then the effects of KIAA0125 on GBC cell migration, invasion, and epithelial-mesenchymal transitions (EMT) were investigated by using a lentivirus-mediated RNA interference (RNAi) system. Notably, cell migration and invasion were strongly inhibited by KIAA0125 suppression. Moreover, the expression of β-Catenin was increased and the expression of Vimentin was decreased in GBC-SD/M cells after KIAA0125 knockdown. Thus, our findings suggested that KIAA0125 promoted the migration and invasion of GBC cells and could serve as a potential therapeutic target in advanced GBC.

This research is aimed at studying the effect of Angelica sinensis polysaccharide (ASP) extracted from the Lixinshui prescription on cardiac disease induced by hypertension in rats. Rat models of cardiovascular disease were established, and the associated factors were measured. The data showed that ASP treatment increased the ejection fraction and short axis shortening rate, while decreasing the LV end-diastolic diameter, LV end-systolic diameter, LV end-diastolic volume, and LV end-systolic volume in HHD rats. ASP downregulated the expression level of TGF-β1, alpha-smooth muscle actin (α-SMA), collagen I, fibronectin, vimentin, Bax, cleaved caspase-9, and cleaved caspase-3 and upregulated the expression level of Bcl-2 in LV of HHD rats. Meanwhile, ASP increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the level of malondialdehyde (MDA), tissue endogenous hydrogen peroxide (H2O2), and reactive oxygen species (ROS). Our findings indicated that ASP could prevent hypertensive heart disease by inhibiting myocardial fibrosis, suppressing the myocardial apoptosis, and alleviating oxidative stress.

Brucea javanica (L.) Merr. is a medicinal herb used in China for the prevention and treatment of diseases such as cancer and malaria. Brusatol was isolated from the seeds of Brucea javanica (L.) Merr, brusatol has a wide range of pharmacological effects, including anti-inflammation and anti-cancer effects.

Hairy enhancer of split-1 (HES1) is a transcriptional target of the Notch pathway, and a high level of HES1 is regarded as a marker of activated Notch. The aim of the study was to investigate the role of HES1 in colorectal cancer progression. We used tissue microarrays to analyze the expression and clinical significance of HES1 in 320 colorectal cancer samples. Stable overexpression and knockdown of HES1 were established in three colorectal cancer cell (CRC) lines (RKO, HCT8 and LOVO). We investigated the differentially expressed genes and enriched pathways in HES1 overexpressing CRC cells by gene expression profiling. Also, the role of HES1 in invasion and migration were examined in vitro and in vivo. We found that high expression of HES1 was significantly correlated with distal metastasis (P = 0.037) at diagnosis, and HES1 could serve as an unfavorable prognostic factor for colorectal cancer patients (P = 0.034). Gene expression profiling and pathway enrichment analysis revealed that HES1 was related to cellular adherens junction loss. In addition, we showed that HES1 overexpression lead to depressed E-cadherin, and elevated N-cadherin, vimentin and Twist-1 levels. Functionally, HES1 enhanced invasiveness and metastasis of CRC cells. HES1 promotes cancer metastasis via inducing epithelial mesenchymal transition and serves as a poor prognosis factor of colorectal cancer patients.

Favorable effects exerted by long-term administration of fingolimod therapy in multiple sclerosis (MS) patients have been reported, but sporadic side effects, such as reversible macular edema, also have been recorded. The present study aimed to determine whether fingolimod therapy is beneficial to the visual system in experimental autoimmune encephalomyelitis (EAE) mice. A decrease in demyelination and axon loss in the optic nerve as well as cellular infiltration, especially the recruited macrophages, was observed in EAE with fingolimod treatment. Fingolimod administration diminished hypergliosis of macroglia, including astrocytes and Müller cells in the retina and optic nerve in EAE. Microglia were hyperactivated in the retina and optic nerve in the EAE mice compared to controls, which could be alleviated by fingolimod treatment. Moreover, apoptosis of retinal ganglion cells (RGC) and oligodendrocytes in the optic nerve was significantly reduced with fingolimod treatment compared to that in the untreated EAE mice. These results suggested that fingolimod exerts neuroprotective and anti-inflammatory effects on the retina and optic nerve in a mouse model of EAE. Considering the paradox of favorable and side effects of fingolimod on visual system, we speculate that side effects including macular oedema caused by fingolimod during MS treatment is tendency to be vasogenic rather than hypergliosis in optic nerve and retina which warrants further neuroophthalmological investigation.

Osteosarcoma (OS) is a malignant bone tumor that frequently occurs in adolescents. It has a high rate of pulmonary metastasis and mortality. Previous studies have demonstrated that human bone marrow mesenchymal stem cells (hBMSCs) can promote the malignant progression in various tumors, including OS. Also, it is recognized that exosomes derived from hBMSCs (hBMSC-Exos) mediate cell-to-cell communication and exhibit similar effects on the development of various tumors. However, the role of hBMSC-Exos in the development of OS is still unclear and the underlying mechanism needs to be elucidated. Our results show that hBMSC-derived exosomes promote OS cell proliferation, migration, and invasion. Meanwhile, silencing autophagy-related gene 5 (ATG5) in OS cells abolishes the pro-tumor effects of hBMSC-Exos in vitro and in vivo. Our present study demonstrates that hBMSC-Exos promotes tumorigenesis and metastasis by promoting oncogenic autophagy in OS.

BACKGROUND Rho GTPase activating protein (RhoGAPs) is an important negative regulator of the Rho signaling pathway that is involved in tumorigenesis in liver, colon, and renal cancer. However, the mechanism by which Rho GTPase activating protein 24 (ARHGAP24) regulates cell invasion and migration of lung cancer has not been fully explained. MATERIAL AND METHODS In this study, ARHGAP24 expression in lung cancer tissues and cell lines was measured by immunohistochemical and Western blot analysis. Transwell or wound healing analysis was performed to detect the cell migration and invasion of ARHGAP24 modulated A549 and NCI-H1975 cells with β-catenin inhibitor XAV-939 (10 µM) treatment, and the expression of MMP9, VEGF, and β-catenin protein was measured by Western blotting. RESULTS Our results showed that ARHGAP24 expression was downregulated in lung cancer tissues and cell lines. pLVX-Puro-ARHGAP24 transfection in A549 cells significantly inhibited cell invasion and migration, along with increased E-cadherin and decreased MMP9, VEGF, Vimentin, and β-catenin protein expression. pLKO.1-ARHGAP24-shRNA transfection in NCI-H1975 cells significantly promoted cell invasion and migration, accompanied with decreased E-cadherin and increased MMP9, VEGF, and β-catenin protein expression. Moreover, NCI-H1975 cells with XAV-939 treatment showed decreased cell invasion and migration when compared with pLKO.1-ARHGAP24-shRNA transfection. ARHGAP24 silencing promoted the transcriptional activity of β-catenin in NCI-H1975 cells. CONCLUSIONS Our findings indicate that ARHGAP24 silencing promotes lung cancer cell migration and invasion through activating β-catenin signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal, and chronic lung disease. There are no effective drug therapies for IPF. Hyperoside, a flavonoid glycoside, has been proven to have anti-inflammatory, anti-fibrosis, antioxidant, and anti-cancer effects. The aim of this study was to explore the role of hyperoside in bleomycin-induced pulmonary fibrosis development in mice. We established the pulmonary fibrosis model by a single intratracheal aerosol injection of bleomycin. Seven days after the bleomycin treatment, the mice were intraperitoneally administered with hyperoside for 14 days. We found that hyperoside treatment ameliorated fibrotic pathological changes and collagen deposition in the lungs of mice with bleomycin-induced pulmonary fibrosis. Hyperoside treatment also reduced the levels of MDA, TNF-α, and IL-6 and increased the activity of SOD. In addition, hyperoside might inhibit the epithelial-mesenchymal transition (EMT) via the AKT/GSK3β pathway. Based on these findings, hyperoside attenuated pulmonary fibrosis development by inhibiting oxidative stress, inflammation, and EMT in the lung tissues of mice with pulmonary fibrosis. Therefore, hyperoside might be a promising candidate drug for the treatment of pulmonary fibrosis.

Recent studies have shown that circular RNA circFLNA is abnormally expressed in a variety of malignant tumors, but its role and mechanism in bladder carcinoma (BCa) are still unclear. The present paper aims to contribute to research on the effects and mechanism of circFLNA on the malignant phenotype of BCa. In this study, the expressions of circFLNA, miR-216a-3p and BTG2 in BCa and BCa cells (EJ, T24, 5637, TCC-SUP) were detected by qRT-PCR. EdU staining, colony formation, Transwell assay, wound healing assays, and sphere formation assay were used to measure the cell proliferation, viability, invasion, migration, and cell stemness of BCa cells after circFLNA overexpression. In addition, the correlation existed between miR-216a-3p and circFLNA or BTG2 was confirmed by Dual-Luciferase Reporter assay and RNA pull-down. Western blot was utilized to determine the expression of BTG2, MMP2, epithelial-mesenchymal transition (EMT)-related proteins (vimentin, E-cadherin) and stem cell-specific proteins (CD34, OCT4, SOX2). Our study confirmed that downregulated circFLNA and BTG2 expression and upregulated miR-216a-3p were found in both BCa tissues and cell lines. Meanwhile, upregulated circFLNA inhibited proliferation, invasion and migration, EMT and stemness of BCa cells. MiR-216a-3p was a target gene of circFLNA and could target BTG2. Further analysis finally demonstrated that circFLNA sponged miR-216a-3p and indirectly promoted BTG2 expression, ultimately regulating proliferation, migration, invasion and EMT of BCa cells. In conclusion, circFLNA inhibits the malignant phenotype of BCa cells and their stemness through miR-216a-3p/BTG2, thus suppressing BCa progression.

Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC. Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines. MTS, luciferase reporter, qRT-PCR, western blot, wound healing, and transwell assays were executed to analyze pathway activity, cell migration, and invasion. Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity. Stimulation of SHh/Gli resulted in EMT signaling, including expression of E-cadherin, N-cadherin, Vimentin, β-catenin, Snail, and Slug, as well as cell cycle progression at mRNA and protein levels in EAC cell lines. Gli inhibition via small molecule administration and siRNA significantly reduced EMT, decreasing cell mobility and invasion. Both Gli and AKT inhibition rescued E-cadherin expression and suppressed AKT phosphorylation. This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility.

We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.

Osteosarcoma (OS) is a common malignant bone cancer. Lactate dehydrogenase B (LDHB) has been revealed to act as a tumor promoter in several cancers. It is also revealed to be correlated with poor prognosis in OS, but its molecular mechanism in OS remains veiled. Our work illustrated that LDHB was overexpressed in OS tissues and cells, and it could enhance cell proliferation, migration, and invasion in OS. Subsequently, it was confirmed that fused in sarcoma (FUS) could bind with LDHB to positively regulate the stability of LDHB messenger RNA (mRNA). Besides, FUS expression was revealed to be elevated in OS tissues and positively correlate with LDHB expression. Furthermore, miR-141-3p, down-regulated in OS cells, was identified as the upstream regulator of FUS in OS cells. Besides, miR-141-3p overexpression decreased mRNA and protein levels of FUS and LDHB. More importantly, overexpression of miR-141-3p could impair FUS overexpression-mediated promotion on LDHB mRNA stability and expression. Finally, rescue assays indicated that miR-141-3p regulated OS cells cellular process via regulating LDHB. In sum, miR-141-3p targets FUS to degrade LDHB, thereby attenuating the malignancy of OS cells.

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.

Gastric cancer (GC) is one of the most frequently diagnosed types of cancer worldwide, and exploring its potential therapeutic targets is particularly important for improving the prognosis of patients with GC. The aim of the present study was to investigate the association between serine/threonine kinase 17a (STK17A) expression and GC prognosis. STK17A expression was measured by quantitative real‑time PCR, western blotting and immunohistochemical staining. Standard stable transfection technology was also used to construct overexpression and knockdown cell lines. Wound healing, Transwell, Cell Counting Kit‑8 and colony formation assays, as well as other methods, were used to explore the function and underlying molecular mechanism of STK17A in GC. The results indicated that STK17A overexpression significantly promoted the proliferation and migration of GC cells. The clinical significance of STK17A in a cohort of 102 cases of GC was assessed by clinical correlation and Kaplan‑Meier analyses. Overexpression of STK17A was demonstrated to be associated with tumor invasion depth (P<0.001), lymph node metastasis (P<0.001) and poor prognosis in terms of 5‑year survival (P<0.001). In addition, Cox multivariate analysis revealed that STK17A expression was an independent risk factor for overall and progress‑free survival (P<0.001). Therefore, STK17A may be a valuable biomarker for the prognosis of patients with GC.

Peyronie's disease (PD) is a severe fibrotic disease of the tunica albuginea that causes penis curvature and leads to penile pain, deformity, and erectile dysfunction. The role of pericytes in the pathogenesis of fibrosis has recently been determined. Extracellular vesicle (EV)-mimetic nanovesicles (NVs) have attracted attention regarding intercellular communication between cells in the field of fibrosis. However, the global gene expression of pericyte-derived EV-mimetic NVs (PC-NVs) in regulating fibrosis remains unknown. Here, we used RNA-sequencing technology to investigate the potential target genes regulated by PC-NVs in primary fibroblasts derived from human PD plaque.