Trail induces cell migration and invasion in apoptosis-resistant cholangiocarcinoma cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for cancer therapy; however, many cholangiocarcinoma cells are resistant to TRAIL-mediated apoptosis. Resistance to apoptosis may unmask TRAIL signaling cascades favoring tumor biology. Thus our aim was to examine whether TRAIL is expressed by human cholangiocarcinomas, and if so, to determine whether it promotes a malignant phenotype. To address this objective, TRAIL expression in human liver specimens was evaluated by immunohistochemistry. The effect of TRAIL on tumor cell migration, invasion, and proliferation was examined in three human cholangiocarcinoma cell lines. TRAIL expression was upregulated by cholangiocytes in preneoplastic disease, primary sclerosing cholangitis, and human cholangiocarcinoma specimens. TRAIL promoted tumor cell migration and invasion but did not induce cell proliferation. TRAIL-mediated cell migration and invasion was NF-kappaB dependent. These data demonstrate that TRAIL promotes cell migration and invasion via a NF-kappaB-dependent pathway in human cholangiocarcinoma cell lines, an observation that has a potential negative implication for TRAIL in cancer therapy.     

CFTR activation suppresses glioblastoma cell proliferation,migration and invasion

The aim of this study was to investigate the function of Cystic fibrosis transmembrane conductance regulator (CFTR) in human glioblastoma (GBM) cells. Data dining results of the Human Protein Atlas showed that low CFTR expression was associated with poor prognosis for GBM patients. We found that CFTR protein expression was lower in U87 and U251 GBM cells than that in normal humane astrocyte cells. CFTR activation significantly reduced GBM cell proliferation. In addition, CFTR activation significantly abrogated migration and invasion of GBM cells. Besides, CFTR activator Forskolin treatment markedly reduced MMP-2 protein expression. These effects of CFTR activation were significantly inhibited by CFTR inhibitor CFTRinh-172 pretreatment. Our findings suggested that JAK2/STAT3 signaling was involved in the anti-glioblastoma effects of CFTR activation. Moreover, CFTR overexpression in combination with Forskolin induced a synergistic anti-proliferative response in U87?cells. Overall, our findings demonstrated that CFTR activation suppressed GBM cell proliferation, migration and invasion likely through the inhibition of JAK2/STAT3 signaling.     

Upregulation of homeobox D10 expression suppresses invasion and migration of clear cell renal cell carcinoma through targeting of E-cadherin

Molecular Biology Reports - Clear cell renal cell carcinoma (CCRCC) is one of the most common types of renal cell carcinoma. Accumulating evidence indicates that homeobox D10 (HOXD10) acts as a...     

MiRNA-145 suppresses lung adenocarcinoma cell invasion and migration by targeting N-cadherin

Objective

To investigate the roles of miR-145 in lung adenocarcinoma (LAC) and to clarify the regulation of N-cadherin by miR-145.

Results

In 57 paired clinical LAC tissues, diminished miR-145 was significantly correlated with the lymph node metastasis and was negatively correlated with N-cadherin mRNA level expression. Wound healing and transwell assays revealed a reduced capability of tumor metastasis induced by miR-145 in LAC. miR-145 negatively regulated the invasion of cell lines through targeting N-cadherin by directly binding to its 3′-untranslated region. Silencing of N-cadherin inhibited invasion and migration of LAC cell lines similar to miR-145 overexpression.

Conclusions

MiR-145 could inhibit invasion and migration of lung adenocarcinoma cell lines by directly targeting N-cadherin.

     

Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment.     

MiRNA-218, a new regulator of HMGB1, suppresses cell migration and invasion in non-small cell lung cancer

MieroRNAs （miRNAs） function as negative regulators of gene expression involved in cancer metastasis. The aim of this study is to investigate the potential roles of miR-218 in non-small cell lung cancer and validate its regulation mech- anism. Functional studies showed that miR-218 overexpres- sion inhibited cell migration and invasion, but had no effect on cell viability. Enhanced green fluorescent protein reporter assay, real-time polymerase chain reaction and western blot analysis confirmed that miR-218 suppressed the expression of high mobility group box-1 （HMGB1） by directly targeting its 31-untranslated region. Accordingly, silencing of HMGBI accorded with the effects of miR-218 on cell migration and invasion, and overexpression of HMGB1 can restore cell migration and invasion which were reduced by miR-218. In conclusion, these findings demon- strate that miR-218 functions as a tumor suppressor in lung cancer. Furthermore, miR-218 may act as a potential thera- peutic biomarker for metastatic lung cancer patients.     

Long non-coding RNA SNHG1 suppresses cell migration and invasion and upregulates SOCS2 in human gastric carcinoma

Gastric carcinoma (GC) is one of the most common malignancies and the third leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. In this study, we investigated the clinical significance and function of lncRNA SNHG1 in GC. SNHG1 was significantly downregulated in GC tumor tissues compared with adjacent noncancerous tissues. Overexpression of SNHG1 in BGC-823 cells remarkably inhibited not only cell proliferation, migration, invasion in vitro, but also tumorigenesis and lung metastasis in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Conversely, inhibition of SNHG1 by transfection of siRNA in AGS cells resulted in opposite phenotype changes. Mechanically, SNHG1 was found interacted with ILF3, NONO and SFPQ. RNA-seq combined with bioinformatic analysis identified a serial of downstream genes of SNHG1, including SOCS2, LOXL2, LTBP3, LTBP4. Overexpression of SNHG1 induced SOCS2 expression whereas knockdown of SNHG1 decreased SOCS2 expression. In addition, knockdown of SNHG1 promoted the activation of JAK2/STAT signaling pathway. Taken together, our data suggested that SNHG1 suppressed aggressive phenotype of GC cells and regulated SOCS2/JAK2/STAT pathway.     

ZBTB38 suppresses prostate cancer cell proliferation and migration via directly promoting DKK1 expression

Prostate cancer is still one of the most common malignancies in men all around the world. The mechanism of how prostate cancer initiates and develops is still not clear. Here in this study, we show that tumor suppressor ZBTB38 could suppress the migration and proliferation of prostate cancer cells. We find lower ZBTB38 expression in prostate cancer tissues, which also strongly predicts a poorer prognosis of prostate cancer. ZBTB38 binds DKK1 (Dickkopf WNT signaling pathway inhibitor 1) locus and promotes DKK1 expression in prostate cancer cell lines. Consistently, reduction of DKK1 expression significantly restores ZBTB38-mediated suppression of migration and proliferation of prostate cancer cell lines. Mechanistically, we find that ZBTB38 primarily binds the promoters of target genes, and differentially regulates the expression of 1818 genes. We also identify PRKDC (protein kinase, DNA-activated, catalytic subunit) as a ZBTB38-interacting protein that could repress the function of ZBTB38 in suppressing migration and proliferation of prostate cancer cells. Taken together, our results indicate that ZBTB38 could repress cell migration and proliferation in prostate cancer via promoting DKK1 expression, and also provide evidence supporting ZBTB38 as a potential prognosis marker for prostate cancer.Subject terms: Tumour-suppressor proteins, Prostate cancer     

miR-335 suppresses migration and invasion by targeting ROCK1 in osteosarcoma cells

Dynamic remodeling of the actin cytoskeleton is crucial for biological processes such as cell migration and cell spreading. S100A10 is a member of the S100 protein family and is involved in intracellular trafficking and cell migration. In this study, we examined the role of S100A10 in actin cytoskeletal organization and cell spreading. Depletion of S100A10 induced disruption of stress fiber formation and delay in cell spreading. Rac1 activation during spreading was suppressed by S100A10 knockdown, and exogenous expression of active Rac1 restored the ability of cells to spread in the absence of S100A10. Our results demonstrate the crucial role of S100A10 in actin dynamics promoting cell spreading via Rac1 activation.     

MUC1 expression is increased during human placental development and suppresses trophoblast-like cell invasion in vitro

Mucin (MUC)1 is a multifunctional mucin expressed by a variety of reproductive tract epithelia. Trophoblast invasion is essential for normal placental development. However, MUC1 expression in the human placenta throughout pregnancy and the role of MUC1 in trophoblast-like cell invasion are still unclear. In the present study, results from quantitative RT-PCR and Western blot demonstrated that MUC1 mRNA and MUC1 protein expression, respectively, increased with gestational age of the human placenta. Immunohistochemistry revealed that MUC1 in placental villi was mainly expressed by syncytiotrophoblasts throughout pregnancy and increased with gestational age. Interestingly, we found two populations of extravillous trophoblasts, MUC1-positive and MUC1-negative cells, in decidua. The numbers of MUC1-positive extravillous trophoblasts were increased during placental development. Furthermore, MUC1 overexpression significantly (P < 0.01) suppressed matrigel invasion of trophoblast-like JAR cells by 34.6% +/- 4.5% compared with control, which was associated with a decrease in MMP9 activity assessed by gelatin zymography. Our results suggest that MUC1 expression in the human placenta is increased during placental development, and its overexpression suppresses trophoblast-like cell invasion in vitro.     

CX3CL1 induces cell migration and invasion through ICAM-1 expression in oral squamous cell carcinoma cells

Human oral squamous cell carcinoma (OSCC) has been associated with a relatively low survival rate over the years and is characterized by a poor prognosis. C-X3-C motif chemokine ligand 1 (CX3CL1) has been involved in advanced migratory cells. Overexpressed CX3CL1 promotes several cellular responses related to cancer metastasis, including cell movement, migration and invasion in tumour cells. However, CX3CL1 controls the migration ability, and its molecular mechanism in OSCC remains unknown. The present study confirmed that CX3CL1 increased cell movement, migration and invasion. The CX3CL1-induced cell motility is upregulated through intercellular adhesion molecule-1 (ICAM-1) expression in OSCC cells. These effects were significantly suppressed when OSCC cells were pre-treated with CX3CR1 monoclonal antibody (mAb) and small-interfering RNA (siRNA). The CX3CL1-CX3CR1 axis activates promoted PLCβ/PKCα/c-Src phosphorylation. Furthermore, CX3CL1 enhanced activator protein-1 (AP-1) activity. The CX3CR1 mAb and PLCβ, PKCα, c-Src inhibitors reduced CX3CL1-induced c-Jun phosphorylation, c-Jun translocation into the nucleus and c-Jun binding to the ICAM-1 promoter. The present results reveal that CX3CL1 induces the migration of OSCC cells by promoting ICAM-1 expression through the CX3CR1 and the PLCβ/PKCα/c-Src signal pathway, suggesting that CX3CL1-CX3CR1-mediated signalling is correlated with tumour motility and appealed to be a precursor for prognosis in human OSCC.     

Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion

No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular d-myo-inositol 1,4,5-trisphosphate and PKCα activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma.     

Downregulation of metallothionein 2A reduces migration,invasion and proliferation activities in human squamous cell carcinoma cells

Molecular Biology Reports - The invasive behaviour of squamous cell carcinoma (SCC), a common malignant tumour of the mouth, is a process mediated by cell proliferation, extracellular matrix...