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.

     

Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells

Background

Molecular profiling of colorectal cancer (CRC) based on global gene expression has revealed multiple dysregulated signalling pathways associated with drug resistance and poor prognosis. However, the role of BMP2 signaling in CRC is not fully characterised.

Methods

Bioinformatics data analysis were conducted on the GSE21510 dataset. Leniviral technology was utilized to stably express BMP2 in the HCT116 CRC model. Gene expression profiling was conducted using Agilent microarray platform while data normalization and bioinformatics were conducted using GeneSpring software. Changes in gene expression were assessed using qRT-PCR. AlamarBlue assay was used to assess cell viability in vitro. In vivo experiments were conducted using SCID mice.

Results

Our data revealed frequent downregulation of BMP2 in primary CRC tissues. Additionally, interrogation of publically available gene expression datasets revealed significant downregulation of BMP2 in metastatic recurrent compared to non-metastatic cancer (p = 0.02). Global gene expression analysis in CRC cells over-expressing BMP2 revealed multiple dysregulated pathways mostly affecting cell cycle and DNA damage response. Concordantly, lentiviral-mediated re-expression of BMP2 inhibited HCT116 CRC growth, sphere formation, clonogenic potential, cell migration, and sensitized CRC cells to 5-fluorouracil (5-FU) in vitro. Additionally, BMP2 inhibited CRC tumor formation in SCID mice.

Conclusions

Our data revealed an inhibitory role for BMP2 in CRC, suggesting that restoration of BMP2 expression could be a potential therapeutic strategy for CRC.

     

High expression of growth factor receptor-bound protein 14 predicts poor prognosis for colorectal cancer patients

Objects

To explore the roles of growth factor receptor-bound protein 14 (GRB14) in colorectal cancer (CRC) and its correlation with clinicopathological characteristics and prognosis of CRC patients.

Results

GRB14 was localized in the cytoplasm of CRC and benign glandular epithelium cells, showing higher levels in CRC tissues compared with normal colon samples (P < 0.001). High GRB14 was associated with a high pathological grade (P = 0.045), advanced clinical stage (P = 0.018), enhanced tumor invasion (P < 0.001) and lymph node metastasis (P = 0.028). The cancer genome atlas (TCGA) mRNA sequence data showed that GRB14 was upregulated in CRC at an advanced clinical stage (P = 0.011) with enhanced tumor invasion (P < 0.001) and lymph node metastasis (P = 0.014). Kaplan–Meier survival curves revealed that CRC patients with high GRB14 levels had a shorter survival compared with those showing low GRB14 expression (P = 0.007). High GRB14 expression was an independent prognostic factor for CRC patients (HR 2.847, 95 %CI 1.058–7.659; P = 0.038).

Conclusions

GRB14 may be an important cancer promoter that enhances CRC progression. Upregulated GRB14 levels may predict a poor clinical outcome in CRC patients.

     

Non-small cell lung cancer: miR-30d suppresses tumor invasion and migration by directly targeting NFIB

Objective

To evaluate the role and the molecular mechanism of miR-30d in non-small cell lung cancer (NSCLC).

Results

qRT-PCR was used to detect miR-30d expression in NSCLC tissues and cell lines. miR-30d was frequently down-regulated in NSCLC and its expression was associated with clinicopathological features of NSCLCC patients. Over-expression of miR-30d notably inhibited cell migration and invasion in NSCLC cell lines. miR-30d could negatively regulate Nuclear factor I B (NFIB) by directly targeting its 3′-UTR, which was confirmed by luciferase assay. NFIB also reversed miR-30d-mediated suppression on the migration and invasion in NSCLC cell lines.

Conclusion

miR-30d suppressed cell migration and invasion by directly targeting NFIB in NSCLC, and NFIB could partially abrogated the inhibition of biological functions by miR-30d.

     

Hypoxia promotes the migration and invasion of human hepatocarcinoma cells through the HIF-1α–IL-8–Akt axis

Background

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown.

Methods

The expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways.

Results

We observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process.

Conclusion

Hypoxia promotes HCC cell migration and invasion through the HIF-1α–IL-8–Akt axis.

     

miR-1260b promotes cell migration and invasion of hepatocellular carcinoma by targeting the regulator of G-protein signaling 22

Objectives

To investigate whether miR-1260b can regulate migration and invasion of hepatocellular carcinoma (HCC) by targeting RGS22.

Results

miR-1260b was up-regulated in HCC tissues compared with their corresponding non-cancerous tissues. Over-expression of miR-1260b increased migration and invasion of HepG2 and SMMC-7721 cells associated with HCC. Regulator of G-protein signaling 22 (RGS22) was identified as a directly target of miR-1260b and was inhibited by miR-1260b. Knockdown of RGS22 increased proliferation of HCC cells.

Conclusions

The new identified miR-1260b/RGS22 axis provides useful therapeutic methods for treatment of HCC deepening on our understanding of underlying mechanisms of HCC tumorigenesis.

     

miR-93 enhances hepatocellular carcinoma invasion and metastasis by EMT via targeting PDCD4

Objectives

To clarify the potential biological function of miR-93 and its related molecular mechanism underlying metastasis in human hepatocellular carcinoma (HCC).

Results

miR-93 was significantly up-regulated in HCC tissues and was associated with poor 5-year overall survival in HCC patients. Transwell assays showed that over-expression of miR-93 increased HCC cell migration and invasion in vitro. Programmed cell death 4 (PDCD4) was a target gene of miR-93 and miR-93 could down-regulate the expression of PDCD4 by directly targeting its 3′-UTR. The re-expression of PDCD4 could attenuate the HCC cell invasion and migration induced by miR-93, while the knockdown of PDCD4 would promote HCC cell migration and invasion via the epithelial-mesenchymal transition (EMT) pathway.

Conclusions

miR-93 provides new insight into the molecular mechanisms of pathogenesis and progression in HCC and offer a potential therapeutic target for the treatment of HCC patients.

     

Metabolomics approach for predicting response to neoadjuvant chemotherapy for colorectal cancer

Introduction

Colorectal cancer (CRC) is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. Only some CRC patients will benefit from neoadjuvant chemotherapy (NACT).

Objectives

An accurate prediction of response to NACT in CRC patients would greatly facilitate optimal personalized management, which could improve their long-term survival and clinical outcomes.

Methods

In this study, plasma metabolite profiling was performed to identify potential biomarker candidates that can predict response to NACT for CRC. Metabolic profiles of plasma from non-response (n?=?30) and response (n?=?27) patients to NACT were studied using UHPLC–quadruple time-of-flight)/mass spectrometry analyses and statistical analysis methods.

Results

The concentrations of nine metabolites were significantly different when comparing response to NACT. The area under the receiver operating characteristic curve value of the potential biomarkers was up to 0.83 discriminating the non-response and response group to NACT, superior to the clinical parameters (carcinoembryonic antigen and carbohydrate antigen 199).

Conclusion

These results show promise for larger studies that could result in more personalized treatment protocols for CRC patients.

     

Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression

Background

Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.

Methods

Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.

Results

Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.

Conclusions

Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

     

MicroRNA-215 enhances invasion and migration by targeting retinoblastoma tumor suppressor gene 1 in high-grade glioma

Objective

To elucidate the molecular mechanism of microRNA-215 (miR-215) in the migration and invasion of high grade glioma.

Results

42 Patients were analysed for clinicopathological characteristics. qRT-PCR showed that miR-215 was up-regulated in glioma tissues compared with non-neoplastic brain tissues (P < 0.05). The up-regulated miR-215 was closely associated with high grade glioma (P < 0.01) and poor overall survival (P < 0.01). Transwell assay showed that re-expression of miR-215 enhanced migration and invasion of glioma cells. miR-215 also down-regulated retinoblastoma tumor suppressor gene 1 (RB1) expression by targeting its 3′-UTR. Reversely, re-expression of RB1 inhibited partial effect of miR-215 on migration and invasion in vitro.

Conclusions

Re-expression of miR-215 promoted cell migration and invasion of glioma by targeting RB1. miR-215 can thus be used as a biomarker for tumor progression and prognosis in human high grade glioma.

     

Distinct differences in serum eicosanoids in healthy,enteritis and colorectal cancer individuals

Background

Eicosanoids as inflammatory mediators take part in the regulation of disease progression. However, the application of serum eicosanoid in disease progression identification was still uncertain.

Methods

Serum from 52 healthy volunteers, 34 enteritis patients and 55 colorectal cancer (CRC) patients were collected. Ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to analyze the change of serum eicosanoids.

Results

Of 158 eicosanoids, we found that lower levels of anti-inflammatory eicosanoids 13-HOTrE, 9-HOTrE, DHA, 11-HETE and 12-HHT were observed in enteritis and CRC group compared with healthy group, meanwhile the content of 5-iPF2α-VI as oxidative stress mediator in enteritis and CRC group was greater than that in healthy groups. Moreover, 9-HODE, 13-HODE, 12,13-diHOME, 8-HETE and 15-HETE were dramatically decrease in CRC group compared with non-CRC group. Additionally, the change of 5-, 12- and 15-HETE content in serum sample was associated with progression from healthy to enteritis, finally to CRC. No significant difference between serum eicosanoids and the expression of CerbB-2 and Ki67 were observed.

Conclusion

Serum eicosanoids might be used as a possible biomarker for identifying among health, enteritis and CRC.

     

The crucial role of SEMA3F in suppressing the progression of oral squamous cell carcinoma

Background

Oral squamous cell carcinoma (OSCC) is one of the most common types of malignancy. Semaphorin 3F (SEMA3F) is highly conserved but present at a lower level in various cancers than in healthy tissues. While it has been reported that SEMA3F is involved in cancer cell proliferation, migration and invasion, its function in OSCC remains unknown.

Methods

The expression of SEMA3F in OSCC tissues and OSCC-derived cells was analyzed using qRT-PCR and western blotting. Using SAS and HSC2 cells, we also monitored the effect of SEMA3F on OSCC cell proliferation, migration and invasion using MTT, colony formation and transwell assays. The function of SEMA3F in OSCC tumor formation was also assessed in vivo.

Results

SEMA3F was significantly downregulated in OSCC tissues and OSCC-derived cells. SEMA3F shows growth inhibitory activity in SAS and HSC2 cells and may act as a tumor suppressor. It can inhibit the migration and invasion potential of OSCC cells. Our results also demonstrate that SEMA3F can suppress the growth of OSCC cells in vivo.

Conclusions

This study revealed that SEMA3F plays a role as a tumor suppressor in OSCC cell proliferation, migration and invasion. Our finding provides new insight into the progression of OSCC. Therapeutically, SEMA3F has some potential as a target for OSCC treatment, given sufficient future research.

     

RNA binding protein Lin28A promotes osteocarcinoma cells progression by associating with the long noncoding RNA MALAT1

Objectives

To explore the effects of Lin28A on progression of osteocarcinoma (OS) cells.

Results

Lin28A mRNA and protein expressions were significantly increased in OS tissues compared with that in normal adjacent tissues. Expressions of Lin28A and long noncoding RNA MALAT1 were positively correlated. Patients with higher Lin28A expression had shorter overall survival. Moreover, Lin28A knockdown inhibited OS cells proliferation, migration, invasion and promoted cell apoptosis; Lin28A was found to harbor binding sites on MALAT1 sequences and associated with MALAT1, and increased MALAT1 stability and expression. Notably, the inhibition of Lin28A knockdown was attenuated or even reversed by MALAT1 overexpression.

Conclusions

RNA binding protein Lin28A could facilitate OS cells progression by associating with the long noncoding RNA MALAT1.

     

TP53INP1 3′-UTR functions as a ceRNA in repressing the metastasis of glioma cells by regulating miRNA activity

Objectives

To explore the effects of the competitive endogenous RNA (ceRNA) network between TP53INP1 and E-cadherin on the invasion and migration of glioma.

Results

TP53INP1 and E-cadherin mRNA and protein were significantly overexpressed in normal brain tissues compared with glioma tissue specimens and correlated with the grades of glioma negatively. The expression of TP53INP1 and E-cadherin were correlated positively. Patients with higher TP53INP1 or E-cadherin expression had longer overall survival. Moreover, TP53INP1 3′-UTR inhibited glioma cell proliferation, invasion and proliferation; Furthermore, the 3′-UTRs of TP53INP1 and E-cadherin harboured seven identical miRNAs binding sites, and TP53INP1 3′-UTR could increase the expression of E-cadherin and decrease the expression of vimentin thus repressing the epithelial-mesenchymal transition (EMT). However, the coding sequence of TP53INP1 could not increase the expression of E-cadherin and the inhibitory effect on EMT of TP53INP1 3′-UTR was reversed by the siRNA against Dicer.

Conclusions

TP53INP1 3′-UTR could inhibit the EMT, thus hindering the migration and invasion of glioma via acting as a ceRNA for E-cadherin.

     

TIPE2 acts as a biomarker for tumor aggressiveness and suppresses cell invasiveness in papillary thyroid cancer (PTC)

Background

Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a newly described negative immune regulator and is closely associated with various tumors. However, the expression and roles of TIPE2 in PTC is unknown.

Results

In the present study, TIPE2 upregulation in PTC tissues was found to be negatively associated with tumor size, capsule infiltration, peripheral infiltration and tumor T stage, which could be used to predict tumor invasiveness. TIPE2 overexpression significantly suppressed the viability, proliferation, migration and invasion of PTC cells. Moreover, TIPE2 suppressed tumor invasiveness by inhibiting Rac1, leading to decreased expression of uPA and MMP9.

Conclusions

These results indicate that TIPE2 is a potential biomarker for predicting tumor aggressiveness and suppresses tumor invasiveness in a Rac1-dependent manner.

     

LncRNA ZEB1-AS1 contributes to STAT3 activation by associating with IL-11 in B-lymphoblastic leukemia

Objective

To investigate the role of lncRNA ZEB1-AS1 in B-lineage acute lymphoblastic leukemia (B-ALL).

Results

ZEB1-AS1 levels were aberrantly up-regulated in B-ALL. All correlated with STAT3 activation and IL-11 production. Moreover, a high level of ZEB1-AS1 predicted poor prognosis of B-ALL patients. Mechanistically, ZEB1-AS1 could bind to IL-11 and promote IL-11 stability. Down-regulation of ZEB1-AS1 decreased IL-11 production of human bone marrow stromal cells (BMSCs), which led to suppressed proliferation and inhibited IL-11/STAT3 pathway in BALL-1 cells.

Conclusions

ZEB1-AS1 promotes the activation of IL-11/STAT3 signaling pathway by associating with IL-11 in B-ALL.

     

Three-dimensional co-culture microfluidic model and its application for research on cancer stem-like cells inducing migration of endothelial cells

Objectives

To build a three-dimensional co-culture model in a microfluidic device for cancer research and evaluate its feasibility by investigating cancer stem-like cells (SCs) induced migration of human umbilical vein endothelial cells (ECs).

Results

The microfluidic device provided two-dimensional and three-dimensional (2D/3D) culture and co-culture environments without affecting cell viability. The device also provided an effective concentration for the chemiotaxis of cells, and to support real-time monitoring of cell behavior. In this model, SCs significantly increased the migration area of ECs with a hepatocarcinoma cell line (MHCC97H; MCs). The presence of ECs also induced both MCs and SCs invasion into Matrigel. The migration area of MCs and SCs significantly increased when co-cultured with ECs.

Conclusions

This 3D co-culture microfluidic model is a suitable model in cancer research. Compared with MCs, SCs had greater potential in inducing EC migration and interacting with ECs.