Wound Closure Promotion by Leucine-Based Pseudo-Proteins: An In Vitro Study.

Our research explores leucine-based pseudo-proteins (LPPs) for advanced wound dressings, focusing on their effects on wound healing in an in vitro model. We assessed three types of LPP films for their ability to enhance wound closure rates and modulate cytokine production. They all significantly improved wound closure compared to traditional methods, with the 8L6 and copolymer films showing the most pronounced effects. Notably, the latter exhibited an optimal cytokine profile: an initial burst of pro-inflammatory TNF-α, followed by a controlled release of IL-6 during the proliferative phase and a significant increase in anti-inflammatory IL-10 during remodeling. This balanced cytokine response suggests that the copolymer film not only accelerates wound closure but also supports a well-regulated healing process, potentially reducing fibrosis and abnormal scarring, underscoring the potential of copolymer LPPs as advanced wound dressing materials. Future research will aim to elucidate the specific signaling pathways activated by the copolymer LPP to better understand its mechanism of action. Overall, LPP films offer a promising approach to improving wound care and could lead to more effective treatments for complex wounds.

Proliferation, migration, and resistance to oxidative and thermal stresses of HT1080 cells with knocked out genes encoding Hsp90α and Hsp90ß.

Heat shock protein 90 (Hsp90) fulfils essential housekeeping functions in the cell associated with the folding, stabilization, and turnover of various proteins. In mammals, there exist two Hsp90 isoforms, stress-inducible Hsp90α and constitutively expressed Hsp90ß. In an attempt to identify cellular processes dependent on Hsp90α and Hsp90ß, we generated a panel of clones of human fibrosarcoma HT1080 cells with the knocked out HSP90AA1 or HSP90AB1 genes encoding, respectively, Hsp90α and Hsp90ß. The knockout of the HSP90AA1 and HSP90AB1 genes practically did not affect cell proliferation and resistance to thermal shock and oxidative stress. The loss of Hsp90α in Hsp90α-null cell clones also did not impair cell migration, while the migration of the Hsp90ß-null cell clones was prominently reduced as compared to parent HT1080 cells. This indicated the necessity of Hsp90ß for efficient basal migration of HT1080 cells whereas Hsp90α seems to be dispensable for this process. The knockout of one Hsp90 isoform was invariably accompanied by an increase in the level of the other Hsp90 isoform by 30-50%, which partly or fully compensated for a decrease in the total level of Hsp90. Thus, we demonstrated the dispensability of Hsp90α and Hsp90ß for HT1080 cells in several cellular processes under normal and stress conditions, which suggested the participation of the two Hsp90 isoforms in the same biological processes and full or at least partial functional substitution of one Hsp90 isoform by the other.

Tormentic acid, a triterpenoid isolated from the fruits of Chaenomeles speciose, protected indomethacin-induced gastric mucosal lesion via modulating miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho a/MLC pathway.

CONTEXT: Tormentic acid (TA), an effective triterpenoid isolated from Chaenomeles speciosa (Sweet) Nakai (Rosaceae) fruits, exerts an effective treatment for gastric damage. OBJECTIVE: To investigate the gastroprotective effect of TA on indomethacin (IND) damaged GES-1 cells and rats, and explore potential mechanisms. MATERIALS AND METHODS: TA concentrations of 1.563-25 µM were used. Cell proliferation, apoptosis and migration were performed using MTT, colony formation, wound healing, migration, Hoechst staining assays. SD rats were divided into control, IND, TA (1, 2 and 4 mg/kg) + IND groups, once a day for 21 continuous days. Twenty-four hours after the last administration, all groups except the control group were given IND (100 mg/kg) by gavage. Gastric juice parameters, gastric ulcer, gastric blood flow (GBF), blood biochemical parameters and cytokine analysis and gastric mucosal histopathology were detected for 2 h and 6 h after IND oral administration. The mRNA and protein expression of miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho A/MLC pathway were analyzed in the IND-damaged GES-1 cells and gastric tissue of rats. RESULTS: TA might ameliorate the gastric mucosal injury by accelerating the IND-damaged GES-1 cell proliferation and migration, ameliorating GBF, ulcer area and pathologic changes, the redox system and cytokine levels, the gastric juice parameters, elevating the gastric pH in IND damaged rats; suppressed miR-139 mRNA expression, elevated CXCR4 and CXCL12 mRNA and protein expression, p-PLC, p-PKC, Rho A, MLCK and p-MLC protein expression. DISCUSSION AND CONCLUSIONS: TA may have potential use as a clinical drug candidate for gastric mucosal lesion treatment.

NLRP2 inhibits cell proliferation and migration by regulating EMT in lung adenocarcinoma cells.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are crucial types of innate immune sensors and well known for their critical roles in the immune system. However, how NLRP2 functions in the progression of cancer is largely unknown. Here, we identified NLRP2 as an antioncogene in lung adenocarcinoma (LUAD) cells. Gain- and loss-of-function studies revealed that NLRP2 silencing promoted cell proliferation and migration by stimulating NF-kB signaling in the microenvironment, which induced epithelial-to-mesenchymal transition (EMT) phenotype and cytoskeleton reorganization in LUAD cells. The addition of the NF-kB inhibitor rescued the function of NLRP2 on EMT. Moreover, NLRP2 increased the level of cofilin phosphorylation and repressed subsequent F-actin reorganization. Consistently, the in vivo study showed that NLRP2 played an inhibitory role in forming metastasis foci. Taken together, NLRP2 inhibited cell proliferation and migration by regulating EMT in LUAD cells, demonstrating the essential function of NLRP2 in the development of LUAD.

Exogenous interleukin-1 beta promotes the proliferation and migration of HeLa cells via the MEK/ERK signaling pathway.

OBJECTIVE: Interleukin-1 beta (IL-1ß) is a crucial cytokine that has been implicated in cancer and metastasis development. However, its possible mechanistic role in cervical cancer remains unclear. This study aimed to investigate the functions of exogenous IL-1ß in cervical cancer cell proliferation and migration. METHODS: HeLa cell proliferation and migration were measured using MTT and Transwell assays. A lentivirus-mediated packaging system was used to construct an IL-1ß overexpressing cell line. MEK/ERK signal transduction was inhibited by pretreatment with the MEK inhibitor PD98059. qRT-PCR and Western blotting were used to test the expression of relevant genes. RESULTS: Exogenous IL-1ß promoted the proliferation and migration of HeLa cells. In addition, overexpression of IL-1ß in HeLa cells promoted cell proliferation. Mechanistically, exogenous IL-1ß increased the phosphorylated MEK and ERK levels in HeLa cells and the expression of JUN, RELB, and NF-κB2. Alternatively, blockade of MEK inhibited the promoting proliferation effects of IL-1ß and the expression of JUN, RELB, and NF-κB2. CONCLUSIONS: Our data suggest that exogenous IL-1ß regulates HeLa cell functions by regulating the MEK/ERK signaling pathway and by targeting JUN, RELB, and NF-κB2. Our study uncovered a potential association across IL-1ß, cervical tumor development, and cancer progression.

Notoginsenoside R1 counteracts mesenchymal stem cell-evoked oncogenesis and doxorubicin resistance in osteosarcoma cells by blocking IL-6 secretion-induced JAK2/STAT3 signaling.

Tumor microenvironment is a critical participant in the initiation, progression and drug resistance of carcinomas, including osteosarcoma. Notoginsenoside R1 (NGR1) is a proverbial active ingredient of the traditional Chinese medicine Panax notoginseng (PN) and possess undeniable roles in several cancers. Nevertheless, its function in osteosarcoma and tumor microenvironment remains elusive. In the current study, exposure to NGR1 dose-dependently inhibited osteosarcoma cell viability and migration, and induced apoptosis. Furthermore, osteosarcoma cells that were incubated with conditioned medium (CM) from bone marrow mesenchymal stem cells (BMSCs) exhibited greater proliferation, migration capacity and MMP-2 and MMP-9 expression relative to control cells, which was reversed when BMSCs were treated with NGR1. Notably, administration with NGR1 antagonized CM-evoked doxorubicin resistance in osteosarcoma cells by decreasing cell viability and increasing cell apoptosis and caspase-3/9 activity. Mechanically, NGR1 suppressed IL-6 secretion from BMSCs, as well as the subsequent activation of the JAK2/STAT3 signaling in osteosarcoma cells. In addition, blocking the JAK2 pathway by its antagonist AG490 reversed CM-induced osteosarcoma cell proliferation, migration and doxorubicin resistance. Moreover, exogenous supplementation with IL-6 engendered not only the reactivation of the JAK2/STAT3 signaling but also muted NGR1-mediated efficacy against osteosarcoma cell malignancy and doxorubicin resistance. Collectively, NGR1 may directly restrain osteosarcoma cell growth and migration, or indirectly antagonize MSC-evoked malignancy and drug resistance by interdicting IL-6 secretion-evoked activation of the JAK2/STAT3 pathway. Consequently, the current study may highlight a promising therapeutic strategy against osteosarcoma by regulating tumor cells and the tumor microenvironment.

Actin polymerization state regulates osteogenic differentiation in human adipose-derived stem cells.

BACKGROUND: Actin is an essential cellular protein that assembles into microfilaments and regulates numerous processes such as cell migration, maintenance of cell shape, and material transport. METHODS: In this study, we explored the effect of actin polymerization state on the osteogenic differentiation of human adipose-derived stem cells (hASCs). The hASCs were treated for 7 days with different concentrations (0, 1, 5, 10, 20, and 50 nM) of jasplakinolide (JAS), a reagent that directly polymerizes F-actin. The effects of the actin polymerization state on cell proliferation, apoptosis, migration, and the maturity of focal adhesion-related proteins were assessed. In addition, western blotting and alizarin red staining assays were performed to assess osteogenic differentiation. RESULTS: Cell proliferation and migration in the JAS (0, 1, 5, 10, and 20 nM) groups were higher than in the control group and the JAS (50 nM) group. The FAK, vinculin, paxillin, and talin protein expression levels were highest in the JAS (20 nM) group, while zyxin expression was highest in the JAS (50 nM) group. Western blotting showed that osteogenic differentiation in the JAS (0, 1, 5, 10, 20, and 50 nM) group was enhanced compared with that in the control group, and was strongest in the JAS (50 nM) group. CONCLUSIONS: In summary, our data suggest that the actin polymerization state may promote the osteogenic differentiation of hASCs by regulating the protein expression of focal adhesion-associated proteins in a concentration-dependent manner. Our findings provide valuable information for exploring the mechanism of osteogenic differentiation in hASCs.

The Unexplored Wound Healing Activity of Urtica dioica L. Extract: An In Vitro and In Vivo Study.

Wound healing is a great challenge in many health conditions, especially in non-healing conditions. The search for new wound healing agents continues unabated, as the use of growth factors is accompanied by several limitations. Medicinal plants have been used for a long time in would healing, despite the lack of scientific evidence veryfying their efficacy. Up to now, the number of reports about medicinal plants with wound healing properties is limited. Urtica dioica L. is a well-known plant, widely used in many applications. Reports regarding its wound healing potential are scant and sparse. In this study, the effect of an Urtica dioica L. extract (containing fewer antioxidant compounds compared to methanolic or hydroalcoholic extracts) on cell proliferation, the cell cycle, and migration were examined. Additionally, antioxidant and anti-inflammatory properties were examined. Finally, in vivo experiments were carried out on full-thickness wounds on Wistar rats. It was found that the extract increases the proliferation rate of HEK-293 and HaCaT cells up to 39% and 30% after 24 h, respectively, compared to control cells. The extract was found to increase the population of cells in the G2/M phase by almost 10%. Additionally, the extract caused a two-fold increase in the cell migration rate of both cell lines compared to control cells. Moreover, the extract was found to have anti-inflammatory properties and moderate antioxidant properties that augment its overall wound healing potential. Results from the in vivo experiments showed that wounds treated with an ointment of the extract healed in 9 days, while wounds not treated with the extract healed in 13 days. Histopathological examination of the wound tissue revealed, among other findings, that inflammation was significantly reduced compared to the control. Urtica dioica L. extract application results in faster wound healing, making the extract ideal for wound healing applications and a novel drug candidate for wound healing.

ANKFY1 is essential for retinal endothelial cell proliferation and migration via VEGFR2/Akt/eNOS pathway.

Dysregulation of endothelial cell proliferation and migration are hallmarks of angiogenic diseases. Among them, excessive ocular angiogenesis is a major cause of blindness. Vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling plays crucial roles in angiogenesis, endothelial cell proliferation and migration. Here, we showed that ankyrin repeat and FYVE domain containing 1 (ANKFY1), a Rab5-GTP-interacting protein, is required for retinal endothelial cell proliferation and migration. ANKFY1 knockdown significantly suppressed cell growth of human retinal microvascular endothelial cells (HRMECs) in the presence or absence of VEGF. HRMEC migration was also inhibited by depletion of ANKFY1. Western blot analysis showed that ANKFY1 knockdown reduced cell surface VEGFR2 level. In contrast, qRT-PCR analysis indicated that ANKFY1 knockdown had no effect on VEGFR2 mRNA levels. We also found that the attenuation of the protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) pathway in ANKFY1 knockdown HRMECs. In conclusion, our findings revealed novel functions of ANKFY1 in cell growth and migration of retinal endothelial cells.

c-Myc-mediated SNRPB upregulation functions as an oncogene in hepatocellular carcinoma.

Dysregulation of genes involved in alternative splicing contributes to hepatocarcinogenesis. SNRPB, a component of spliceosome, is implicated in human cancers, yet its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. Here, we show that SNRPB expression is increased in HCC tissues, compared with the nontumorous tissues, at both messenger RNA and protein levels in two independent cohorts. High expression of SNRPB is significantly associated with higher pathological grade, vascular invasion, serum alpha-fetoprotein level, tumor metastasis, and poor disease-free and overall survivals. Luciferase reporter and chromatin immunoprecipitation assays demonstrate that SNRPB upregulation in HCC is mediated by c-Myc. Positive correlation is found between SNRPB and c-Myc expression in clinical samples. In vitro studies show that ectopic expression of SNRPB promotes HCC cell proliferation and migration, whereas knockdown of SNRPB results in the opposite phenotypes. Collectively, our data suggest SNRPB function as an oncogene and serve as a potential prognostic factor in HCC.

Multiple functions of thymosin ß4 in the pearl oyster Pinctada fucata suggest its multiple potential roles in artificial pearl culture.

Thymosin ß4 is a multifunctional protein in vertebrates that participates in physiological processes, such as wound healing, immune response, cell proliferation and migration. We assessed the multifarious roles of this small peptide in Pinctada fucata, an oyster commonly used in pearl culture in China. Our results showed that when P. fucata was challenged by bacterial pathogens or LPS, the relative expression level of Pfthymosin ß4 mRNA was significantly up-regulated, suggesting its involvement in immune response of the animal. Recombinant Pfthymosin ß4 (rPfthymosin ß4) was produced and showed in vitro different antibacterial activities against different pathogenic bacteria; the inhibitory effect of rPfthymosin ß4 on bacterial growth was relatively stronger in the broth culture than agar culture. The overexpression of Pfthymosin ß4 in Escherichia coli BL21(DE3) cells could improve their resistance to Cu2+, Zn2+, Cd2+, and H2O2, suggesting that Pfthymosin ß4 is likely involved with antioxidant. rPfthymosin ß4 also significantly promoted the proliferation and migration of mouse aortic vascular smooth muscle cells as indicated by MTT assay and cell scratch assay, respectively. In addition, chemically synthesized or recombinant Pfthymosin ß4 could transiently increase the circulating total hemocytes counts but down-regulated by RNAi in P. fucata. Taking together above results and previous studies suggested that Pfthymosin ß4 is potentially able to promote wound healing through enhancing antibacterial activity and antioxidant capacity, promotion of cell proliferation and migration, and increase of circulating hemocytes in P. fucata due to nucleus implantation injury. Thus, the future of recombinant Pfthymosin ß4 should be promising in the culture of pearls in P. fucata.

The expression and significance of mTORC1 in diabetic retinopathy.

BACKGROUND: To investigate the expression and significance of mechanistic target of rapamycin complex 1(mTORC1) in diabetic retinopathy (DR), and to find new targets and new methods for the treatment of DR. METHODS: A DR rat model was prepared by general feeding combined with intraperitoneal injection of 10% streptozotocin (60 mg/kg). The rats were randomly divided into a control group (NDM group) and a diabetes group (DM group). Three months later, the degrees of retinopathy was determined using hematoxylin and eosin staining, and the levels of p-S6, VEGF, and PEDF proteins were detected by immunohistochemistry and western blotting. Human retinal capillary endothelial cells (HRCECs) were cultured in high glucose (HG) conditions, then treated with rapamycin or transfected with siTSC1.The protein levels of p-S6 were assessed by western blotting. The 5-ethynyl-2'-deoxyuridine assay was used to detect cell proliferation, and the Transwell assay was used to detect cell migration. RESULTS: A DM rat model was successfully developed. The expressions of p-S6 and VEGF proteins were significantly increased in the DM group (p < 0.05), and the expression of PEDF protein was significantly decreased compared with the NDM group (p < 0.05). In vitro, the p-S6 protein, as well as cell proliferation and migration, in HG induced HRCECs were increased (p < 0.05) compared with the control (normal glucose) group (p < 0.05). After transfection with siTSC1 to activate mTORC1, the expression of p-S6, as well as cell proliferation and migration, were increased. In contrast, rapamycin decreased p-S6 expression, as well as proliferation and migration, in HG induced HRCECs compared to the control group (p < 0.05). CONCLUSION: mTORC1 plays an important role in DR. After activation, mTORC1 induced expression of the p-S6 protein, regulated the expressions of VEGF and PEDF proteins, and changed the proliferation and migration of endothelial cells. The mTORC1 can therefore be used as a new target,as well as in the treatment of DR.

STRIP2 silencing inhibits vascular smooth muscle cell proliferation and migration via P38-AKT-MMP-2 signaling pathway.

STRIP2 (FAM40B) was reported to regulate tumor cell migration. Our study aims to discuss the effect of STRIP2 in mouse aortic smooth muscle cell (MOVAS) proliferation and migration processes, which contributes greatly to atherosclerosis formation. In MOVAS cells, STRIP2 depletion suppressed cell proliferation and migration, which were related to a remarkable decrease in matrix metalloproteinases-2 (MMP-2)/MMP-9 expression. Additionally, P38 mitogen-activated protein kinases and Protein kinase B (AKT) are inactivated while extracellular signal-regulated kinase (ERK1/2) and jun N-terminal kinase (JNK) are activated upon STRIP2 silencing. SB203580 (P38 inhibitor) further reduced AKT phosphorylation (p-AKT) while dehydrocorydaline chloride (Dc; P38 activator) reversed this effect. Furthermore, Dc significantly recovered MMP-2 expression in STRIP2-knockdown cells. As expected, overexpressing STRIP2 exhibited a contrary effect. Dc and AKT activator SC79 reversed the inhibition of cell proliferation and migration induced by STRIP2 silencing. Interestingly, STRIP2 depletion increased vascular endothelial growth factor level significantly. Taken together, STRIP2 contributed to cell proliferation and migration through P38-AKT-MMP-2 signaling in MOVAS cells, indicating the importance of STRIP2 in atherosclerosis.

LncRNA AWPPH inhibits SMAD4 via EZH2 to regulate bladder cancer progression.

This study aimed to investigate the effect and underlying mechanism of lncRNA AWPPH in bladder cancer (BC). A total of 20 Ta-T1 stage BC tissues, 20 T2-T4 stage BC tissues, and 20 normal bladder tissues, as well as human bladder epithelial cell line SV-HUC-1, human BC cell lines RT4, and T24 were obtained to detect the levels of AWPPH, enhancer of zeste homolog 2 (EZH2) and SMAD4 using RT-qPCR or Western blotting. RT4 cells were transfected with pc-AWPPH, pc-EZH2, or pc-control and T24 cells were transfected with si-AWPPH, si-EZH2, si-control, or pc-AWPPH + pc-SMAD4, respectively. Then, cell proliferation, apoptosis, autophagy, and migration, were detected using MTT assay, colony formation assay, Annexin V-FITC/PI method, Western blotting, and Transwell analysis, respectively. The relationship of AWPPH and EZH2 or SMAD4 was evaluated by RNA immunoprecipitation (RIP) assay or Chromatin immunoprecipitation (ChIP) assay. Compared with normal bladder tissues or cells, the levels of AWPPH and EZH2 were overexpressed, while SMAD4 was down-regulated in BC tissues or cells (all P < 0.01). Cell viability, colony number, and migration were significantly increased, while cell apoptosis ratio was reduced in cells with pc-AWPPH compared with cells with pc-control (all P < 0.05), meanwhile, these effects were reversed by the treatment of pc-SMAD4. Then, RIP assay revealed that AWPPH could bind to EZH2 and ChIP assay showed SMAD4 was regulated by EZH2. LncRNA AWPPH can promote cell proliferation, autophagy, and migration, as well as inhibit cell apoptosis in BC by inhibiting SMAD4 via EZH2.

Protective Effect of Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava on Monocyte-Associated Vascular Dysfunction.

Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation.

Aberrant nitric oxide synthase 2 (NOS2) expression has been suggested as an interesting therapeutic target that is being implicated as a component of the molecular profile of several human malignant tumors, including glioblastoma, which is the most aggressive brain tumor with limited therapeutic options and poor prognosis. The aim of the present work was to evaluate the effect of 1400W, a specific NOS2 inhibitor, on human glioma cells in terms of clonogenic potential, proliferation, migration rate, and neurosphere generation ability. NOS2 expression was determined by Western blotting. Nitric oxide (NO) production was measured through nitrite level determination. The trypan blue exclusion test and the plate colony formation assay were performed to evaluate cell proliferation and clonogenic potential. Cell proliferation and migration ability was assessed by the in vitro wound-healing assay. Neurosphere generation in a specific stemcell medium was investigated. NOS2 was confirmed to be expressed in both the glioma cell line and a human glioma primary culture, and overexpressed in relative derived neurospheres. Experiments that aimed to evaluate the influence of 1400W on U-87 MG, T98G (glioblastoma cell lines) and primary glioma cells sustained the crucial role played by NOS2 in proliferation, colony formation, migration, and neurosphere generation, thus supporting the emerging relevance of a NOS2/NO system as a prognostic factor for glioma malignancy and recurrence.

miR-139 is up-regulated in osteoarthritis and inhibits chondrocyte proliferation and migration possibly via suppressing EIF4G2 and IGF1R.

Osteoarthritis (OA) is one of the most progressive articular cartilage erosions. microRNAs (miRNAs) play pivotal roles in OA modulation, but the role of miR-139 in OA remains elusive. This study aims to reveal the effects and possible mechanism of miR-139 in OA and chondrocytes. The levels of miR-139 and its possible targets eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) and insulin-like growth factor 1 receptor (IGF1R) were detected by qRT-PCR in the articular cartilages of 20 OA patients and 20 non-OA patients. Human chondrocyte CHON-001 cells were transfected with miR-139 mimic or inhibitor, as well as the siRNAs of EIF4G2 and IGF1R. Cell viability by MTT assay, proliferation by colony formation assay and migration by Transwell assay were performed. Results showed that miR-139 was up-regulated, while EIF4G2 and IGF1R mRNAs down-regulated in OA cartilages (P < 0.001), and negative correlations existed between the level of miR-139 and EIF4G2 or IGF1R. Overexpression of miR-139 in CHON-001 cells suppressed both mRNA and protein levels of EIF4G2 and IGF1R, and inhibited cell viability, colony formation number and cell migration, while miR-139 inhibitor induced the opposite effects. Knockdown of EIF4G2 or IGF1R in CHON-001 cells reversed the effects of miR-139 inhibitor on cell viability, colony formation and cell migration. These results indicate that miR-139 is capable of inhibiting chondrocyte proliferation and migration, thus being a possible therapeutic target for OA. The mechanism of miR-139 in chondrocytes may be related to its regulation on EIF4G2 and IGF1R.

Activated cdc42-associated kinase is up-regulated in non-small-cell lung cancer and necessary for FGFR-mediated AKT activation.

Activated cdc42-associated tyrosine kinase 1 (ACK1) has been reported to be implicated in non-small-cell lung cancer (NSCLC). However, the expression pattern and biological functions of ACK1 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of ACK1 was significantly up-regulated in NSCLC samples compared to their adjacent normal tissues. Meanwhile, the expression of ACK1 was inversely correlated with the survival of NSCLC patients. Moreover, in the biological function studies, ACK1 was further validated to promote the growth, migration, and metastasis of NSCLC cells in vitro and in vivo. Mechanistically, ACK1 bind with FGFR1 and was essential for the phosphorylation of AKT induced by FGF. Our study demonstrated that ACK1 played an oncogenic role in the progression of NSCLC and ACK1 might be a promising target for the treatment of NSCLC.

Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells.

Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca(2+) entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing the activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca(2+) entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. An overexpression of TRPM7 significantly facilitated cholesterol dependent Ca(2+) entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol-mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer.

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression.

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.