Gene Summary

Gene:POSTN; periostin
Aliases: PN, OSF2, OSF-2, PDLPOSTN
Summary:This gene encodes a secreted extracellular matrix protein that functions in tissue development and regeneration, including wound healing, and ventricular remodeling following myocardial infarction. The encoded protein binds to integrins to support adhesion and migration of epithelial cells. This protein plays a role in cancer stem cell maintenance and metastasis. Mice lacking this gene exhibit cardiac valve disease, and skeletal and dental defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: POSTN (cancer-related)

Wang Q, Yu W, Huang T, et al.
RUNX2 promotes hepatocellular carcinoma cell migration and invasion by upregulating MMP9 expression.
Oncol Rep. 2016; 36(5):2777-2784 [PubMed] Related Publications
Runt-related transcription factor 2 (RUNX2) was first identified as a transcription factor to play an important role in different biological processes of osteoblast and chondrocyte, including differentiation and migration. Recently, RUNX2 has been implicated in promigratory/proinvasive behavior in different human malignancies. In the present study, we demonstrated that the RUNX2 mRNA and protein expression were both increased significantly in HCC tissues and cell lines. High RUNX2 expression was correlated obviously with poor clinicopathological characteristics including multiple tumor nodes, high histological grading, venous infiltration and advanced tumor-node-metastasis (TNM) stage. In addition, we demonstrated that RUNX2 was a prognostic indicator for predicting 5-year overall survival and disease-free survival of HCC patients. Our studies showed that RUXN2 overexpression promoted, while RUNX2 knockdown inhibited HCC cell migration and invasion in vitro. Notably, RUNX2 positively regulated matrix metalloproteinase 9 (MMP9) accumulation in HCC cells. Furthermore, we confirmed that RUNX2 was positively correlated with MMP9 expression in HCC tissues by Pearson correlation analysis. Mechanistically, we demonstrated that MMP9 overexpression increased HCC cell migration and invasion, while MMP9 knockdown reduced HCC cell migration and invasion in vitro. Alteration of MMP9 expression partially abrogated the effects of RUNX2 on HCC cell migration and invasion, which suggests that RUNX2 developed its pro-metastatic biological function by upregulating the expression of MMP9 in HCC cells. In conclusion, our results reveal that RUNX2 promotes HCC cell migration and invasion by MMP9-mediated pathway, and potentially serves as a new prognostic biomarker and in therapeutic strategies for HCC.

Liu G, Wu K, Sheng Y
Elucidation of the molecular mechanisms of anaplastic thyroid carcinoma by integrated miRNA and mRNA analysis.
Oncol Rep. 2016; 36(5):3005-3013 [PubMed] Related Publications
To elucidate the complex molecular mechanisms of anaplastic thyroid carcinoma (ATC), the mRNA and miRNA expression profiles of ATC were systematically explored. A total of 55 common differentially expressed genes (DEGs) were obtained from two mRNA expression datasets including 23 ATC samples and 24 paired normal samples. Gene expression levels of three randomly selected DEGs, VCAN, COL5A1 and KCNJ16, were examined using RT-PCR in 10 ATC samples. Notably, the ATC and normal samples were clearly classified into two groups based on their common DEGs. Moreover 23 common DEGs, such as TG, NKX2-1, KCNJ16 and CTHRC1, were predicted to be the potential targets of 17 identified miRNAs in ATC. Meanwhile, several miRNA target genes were associated with biological processes related to tumor progression such as angiogenesis, cell migration or growth and potassium channel regulation. In summary, the poor prognosis of ATC is possibly caused via complex biological processes. Firstly, angiogenesis was activated by the high expression of CTHRC1, VCAN and POSTN, providing necessary nutrition for tumor cells. Then tumor distant metastasis was induced via stimulation of cell migration and cell growth or regulation of cell-cell interaction. Moreover, intracellular potassium concentration changes promoted ATC progression indirectly. Hence, identification of these critical DEGs was valuable in understanding the molecular mechanisms of ATC.

Liu Y, Li F, Gao F, et al.
Periostin promotes the chemotherapy resistance to gemcitabine in pancreatic cancer.
Tumour Biol. 2016; 37(11):15283-15291 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths. The nucleoside analog gemcitabine has been the cornerstone of adjuvant chemotherapy in PDAC for decades. However, gemcitabine resistance develops within weeks of chemotherapy initiation, which might be intrinsic to cancer cells and influenced by tumor microenvironment. Recently, pancreatic stellate cells (PSCs) have greatly increased our attention on tumor microenvironment-mediated drug resistance. Periostin is exclusively overexpressed in PSCs and the stroma of PDAC creating a tumor-supportive microenvironment in the pancreas. However, whether periostin contributed to chemoresistance in PDAC remains unknown. Therefore, we focused on the role of periostin in PDAC by observing the effects of silencing this gene on gemcitabine resistance in vitro and in vivo aiming to explore the possible molecular mechanism. In this study, the pancreatic cancer cell (PCC) proliferation and apoptosis were assayed to investigate the sensitivity to gemcitabine after silencing periostin. We provide the evidence that periostin not only drives the carcinogenic process itself but also significantly associated with gemcitabine-induced apoptosis. These findings collectively indicated that periostin increases the chemoresistance to gemcitabine. Thus, targeting periostin might offer a new opportunity to overcome the gemcitabine resistance of PDAC.

Matsumura Y, Hiraoka K, Ishikawa K, et al.
CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis.
Anticancer Res. 2016; 36(9):4467-75 [PubMed] Related Publications
BACKGROUND: The co-stimulatory molecule cluster of differentiation 40 (CD40) is widely expressed in various types of malignant tumors, but its role remains unclear. The purpose of this study was to investigate the relationship between CD40 expression and clinicopathological variables in patients with esophageal squamous cell carcinoma (ESCC), as well as the function of CD40 expressed on ESCC tumor cells in vitro.
MATERIALS AND METHODS: Tumor specimens of patients who underwent surgical resection for ESCC were immunohistochemically analyzed for CD40 expression.
RESULTS: Of the 122 specimens, 45 (37%) were positive for CD40. Significant positive correlation was found between CD40 expression and p-stage (p=0.0011), histopathological grade (p=0.0143), pT-classification (p=0.0011), and pN-classification (p=0.0007). Survival of patients with stage III and IV disease with positive CD40 expression was significantly shorter than that of those with negative expression (log-rank test, p=0.0422). In in vitro analysis, while the addition of recombinant human CD154 did not inhibit growth, it did induce a significant increase in interleukin 6 production in ESCC cell lines.
CONCLUSION: These results suggest that functional expression of CD40 on tumor cells might play an important role in tumor progression and lymph node metastasis in ESCC.

Mays AC, Chou J, Craddock AL, et al.
Gene Variability Between Perineural-positive and Perineural-negative Squamous Cell Skin Cancers.
Anticancer Res. 2016; 36(8):4007-11 [PubMed] Related Publications
AIM: To identify differentially expressed genes (DEGs) between perineural invasion-positive (PP) and -negative (PN) cutaneous squamous cell cancers (CSCC).
MATERIALS/METHODS: Forty CSCC samples with and without perineural invasion were processed for RNA isolation and hybridization to Affymetrix-U219 DNA microarrays. Raw gene expression data were normalized by Robust Multi-array Averaging (RMA) and log2 transformed. Gene expression-based classification models were created and accuracies evaluated using leave-one-out cross-validation.
RESULTS: At a stringent limma p-value (p<0.001), 24 genes were differentially expressed between PP and PN samples. The cross-validated performance of the eight classification models exhibited a mean accuracy of 85-95%. Diagonal linear discriminant was most accurate at 95%, followed by Bayesian compound covariate at 94%. The poorest accuracy (85%) was observed for 1-Nearest neighbor and Support vector machines.
CONCLUSION: Gene expression may distinguish between PP and PN CSCC. Understanding these gene patterns may potentiate more timely diagnosis of perineural invasion and guide comprehensive therapies.

Lian S, Shi R, Huang X, et al.
Artesunate attenuates glioma proliferation, migration and invasion by affecting cellular mechanical properties.
Oncol Rep. 2016; 36(2):984-90 [PubMed] Related Publications
Glioma is one of the most common malignant brain tumors. Current chemotherapy is far from providing satisfactory clinical outcomes for patients with glioma. More efficient drugs are urgently needed. Artesunate (ART) is clinically used as an anti-malarial agent and exhibits potent antiproliferative activity as a traditional Chinese medicine. In addition, ART has been shown to exert a profound cytotoxic effect on various tumor cell lines, presenting a novel candidate for cancer chemotherapy. However, its anticancer effect on glioma by altering cell biomechanical properties remains unclear. The present study aimed to identify the anticancer effects of ART on human glioma SHG44 cells by assessing cell proliferation, migration/invasion, the expression of claudin-1 and the biomechanical properties of ART-treated SHG44 cells. The proliferation of the SHG44 cells was assessed by MTT assay. The cell apoptosis was detected by flow cytometry. For cell migration and invasion assays, the Transwell was used. The expression of the gene claudin-1 was detected by polymerase chain reaction. The cell membrane and biomechanical properties, as targets of ART action, were investigated by atomic force microscopy (AFM). ART significantly inhibited the proliferation of SHG44 cells in a dose- and time-dependent manner. After treatment with 30 mg/l ART, the level of cell apoptosis was significantly increased (from 6.88±0.062 to 23.7±4.16%). Furthermore, the cell migration and invasion abilities of the SHG44 cells were markedly inhibited after treatment with 30 mg/l ART. Compared with the control group (0 mg/l ART), the SHG44 cells treated with 30 mg/l ART exhibited upregulated expression of claudin-1, increased adhesive force (from 2,400±300 to 3,600±500 pN), increased high connection among SHG44 cells, increased cytomembrane roughness (from 0.118±0.011 to 0.269±0.015 µm) and reduced elasticity (from 23±8 to 3.5±1.1 MPa). The present study demonstrated that ART could alter the biomechanical properties of the glioma cells to inhibit cell proliferation, migration and invasion.

Li1 XH, Yang CZ, Wang J
Network spatio-temporal analysis predicts disease stage-related genes and pathways in renal cell carcinoma.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
The purpose of this study was to screen the key genes and pathways of renal cell carcinoma (RCC) and lay the foundation for its diagnosis and therapy. Microarray data of normal subjects and RCC patients at different stages of disease were used to screen differentially expressed genes (DEGs). Based on the DEGs in the four disease stages, four co-expression networks were constructed using the Empirical Bayes method and hub genes were obtained by centrality analysis. The enriched pathways of the DEGs and the mutual hub genes in the cluster of each disease stage were investigated. The mutual hub genes of the four disease stages in RCC tissue were validated using reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. A total of 432 DEGs were screened, including 233 upregulated and 199 downregulated genes, by statistical analysis. Centrality analysis of co-expression networks in different disease stages suggested that PLXDC1, IKZF1, RUNX2, and RNF125 were mutual hub genes. Pathway analysis showed that the DEGs were significantly enriched in seven terms. The hub modules in stage I disease were significantly enriched in the complement coagulation cascade pathway and the hub modules of the other three disease stages were enriched in natural killer cell-mediated cytotoxicity. The expression levels of PLXDC1, IKZF1, RUNX2, and RNF125 were significantly different between normal subjects and RCC patients by RT-PCR and western blot. Our study revealed four hub genes (PLXDC1, IKZF1, RUNX2, and RNF125) and two biological pathways that might be underlying biomarkers involved in RCC.

Viloria K, Hill NJ
Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation.
Biomol Concepts. 2016; 7(2):117-32 [PubMed] Related Publications
Matricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes. Alternative splicing is a precisely regulated process that can produce multiple isoforms with variable functions from a single gene. To date, the expression of alternate transcripts for the matricellular family has been reported for only a handful of genes. Here we analyse the evidence for alternative splicing across the matricellular family including the secreted protein acidic and rich in cysteine (SPARC), thrombospondin, tenascin and CCN families. We find that matricellular proteins have double the average number of splice variants per gene, and discuss the types of domain affected by splicing in matricellular proteins. We also review the clinical significance of alternative splicing for three specific matricellular proteins that have been relatively well characterised: osteopontin (OPN), tenascin-C (TNC) and periostin. Embracing the complexity of matricellular splice variants will be important for understanding the sometimes contradictory function of these powerful regulatory proteins, and for their effective clinical application as biomarkers and therapeutic targets.

Ertao Z, Jianhui C, Chuangqi C, et al.
Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway.
J Exp Clin Cancer Res. 2016; 35:63 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.
METHODS: SHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.
RESULTS: SHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95% CI: 1.109-2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.
CONCLUSIONS: Increased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.

Zheng QM, Lu JJ, Zhao J, et al.
Periostin Facilitates the Epithelial-Mesenchymal Transition of Endometrial Epithelial Cells through ILK-Akt Signaling Pathway.
Biomed Res Int. 2016; 2016:9842619 [PubMed] Free Access to Full Article Related Publications
Although periostin was confirmed to facilitate the pathogenesis of endometriosis by enhancing the migration, invasion, and adhesion of human endometrial stromal cells (ESCs), its effect on the endometrial epithelial cells (EECs) is still unknown. The current study aimed to determine whether periostin enhanced the epithelial-mesenchymal transition (EMT) of EECs. EECs were isolated from 12 women with endometriosis. The migration and invasion abilities of EECs were evaluated by transwell assays. Expressions of proteins were detected by western blot. After treatment with periostin, the migration and invasion abilities of EECs were enhanced. Additionally, E-cadherin and keratin were downregulated while N-cadherin and vimentin were upregulated in EECs. Simultaneously, levels of ILK, p-Akt, slug, and Zeb1 were all upregulated in EECs. After silencing the expression of ILK in EECs, levels of p-Akt, slug, Zeb1, N-cadherin, and vimentin were downregulated while E-cadherin and keratin were upregulated. Although periostin weakened the above effects in EECs after silencing the expression of ILK, it failed to induce the EMT of EECs. Thus, periostin enhanced invasion and migration abilities of EECs and facilitated the EMT of EECs through ILK-Akt signaling pathway. Playing a pivotal role in the pathogenesis of endometriosis, periostin may be a new clinical therapy target for endometriosis.

Liu GX, Xi HQ, Sun XY, et al.
Isoprenaline Induces Periostin Expression in Gastric Cancer.
Yonsei Med J. 2016; 57(3):557-64 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Periostin mediates critical steps in gastric cancer and is involved in various signaling pathways. However, the roles of periostin in promoting gastric cancer metastasis are not clear. The aim of this study was to investigate the relevance between periostin expression and gastric cancer progression and the role of stress-related hormones in the regulation of cancer development and progression.
MATERIALS AND METHODS: Normal, cancerous and metastatic gastric tissues were collected from patients diagnosed with advanced gastric cancer. The in vivo expression of periostin was evaluated by in situ hybridization and immunofluorescent staining. Meanwhile, human gastric adenocarcinoma cell lines MKN-45 and BGC-803 were used to detect the in vitro expression of periostin by using quantitative real-time polymerase chain reaction (PCR) and western blotting.
RESULTS: Periostin is expressed in the stroma of the primary gastric tumors and metastases, but not in normal gastric tissue. In addition, we observed that periostin is located mainly in pericryptal fibroblasts, but not in the tumor cells, and strongly correlated to the expression of α-smooth muscle actin (SMA). Furthermore, the distribution patterns of periostin were broader as the clinical staging of tumors progressed. We also identified a role of stress-related signaling in promoting cancer development and progression, and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells.
CONCLUSION: These findings suggest that the distribution pattern of periostin was broader as the clinical staging of the tumor progressed and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells.

Hu W, Jin P, Liu W
Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin.
Cell Physiol Biochem. 2016; 38(3):1199-208 [PubMed] Related Publications
BACKGROUND/AIMS: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC.
METHODS: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model.
RESULTS: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin-silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors.
CONCLUSION: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.

Liao CT, Chen SJ, Lee LY, et al.
An Ultra-Deep Targeted Sequencing Gene Panel Improves the Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma.
Medicine (Baltimore). 2016; 95(8):e2751 [PubMed] Free Access to Full Article Related Publications
An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN+) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group.A mutation-based signature affecting 10 genes (including genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN+ OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS-positive. The 5-year locoregional control, distant metastases, disease-free, disease-specific, and overall survival (OS) rates served as outcome measures.The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P = 0.0067), distant metastases (P = 0.0001), DFS (P < 0.0001), disease-specific survival (DSS, P < 0.0001), and OS (P = 0.0003) in pN+ OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001). Among ECS-negative patients, those with a UDT-Seq-positive panel (n = 31) had significantly worse DFS (P = 0.0005) and DSS (P = 0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n = 46) also had significantly worse DFS (P = 0.0032) and DSS (P = 0.0098).Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence.

Shin MH, He Y, Marrogi E, et al.
A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells.
PLoS Genet. 2016; 12(2):e1005884 [PubMed] Free Access to Full Article Related Publications
The inactivation of p53 creates a major challenge for inducing apoptosis in cancer cells. An attractive strategy is to identify and subsequently target the survival signals in p53 defective cancer cells. Here we uncover a RUNX2-mediated survival signal in p53 defective cancer cells. The inhibition of this signal induces apoptosis in cancer cells but not non-transformed cells. Using the CRISPR technology, we demonstrate that p53 loss enhances the apoptosis caused by RUNX2 knockdown. Mechanistically, RUNX2 provides the survival signal partially through inducing MYC transcription. Cancer cells have high levels of activating histone marks on the MYC locus and concomitant high MYC expression. RUNX2 knockdown decreases the levels of these histone modifications and the recruitment of the Menin/MLL1 (mixed lineage leukemia 1) complex to the MYC locus. Two inhibitors of the Menin/MLL1 complex induce apoptosis in p53 defective cancer cells. Together, we identify a RUNX2-mediated epigenetic mechanism of the survival of p53 defective cancer cells and provide a proof-of-principle that the inhibition of this epigenetic axis is a promising strategy to kill p53 defective cancer cells.

Nuzzo PV, Rubagotti A, Zinoli L, et al.
The prognostic value of stromal and epithelial periostin expression in human breast cancer: correlation with clinical pathological features and mortality outcome.
BMC Cancer. 2016; 16:95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PN is a secreted cell adhesion protein critical for carcinogenesis. In breast cancer, it is overexpressed compared to normal breast, and a few reports suggest that it has a potential role as a prognostic marker.
METHODS: Tumour samples obtained at the time of mastectomy from 200 women followed for a median time of 18.7 years (range 0.5-29.5 years) were investigated through IHC with a polyclonal anti-PN antibody using tissue microarrays. Epithelial and stromal PN expression were scored independently according to the percentage of coloured cells; the 60th percentile of PN epithelial expression, corresponding to 1%, and the median value of PN stromal expression, corresponding to 90%, were used as arbitrary cut-offs. The relationships between epithelial and stromal PN expression and clinical-pathological features, tumour phenotype and the risk of mortality following surgery were analysed. Appropriate statistics, including the Fine and Gray competing risk proportional hazard regression model, were used.
RESULTS: The expression of PN in tumour epithelial cells was significantly lower than that which was observed in stromal cells (p < 0.000). No specific association between epithelial or stromal PN expression and any of the clinical-pathological parameters analysed was found as it was observed in respect to mortality when these variables were analysed individually. However, when both variables were considered as a function of the other one, the expression of PN in the stromal cells maintained a statistically significant predictive value with respect to both all causes and cancer-specific mortality only in the presence of high epithelial expression levels. No significant differences in either all causes or BCa-specific mortality rates were shown according to epithelial expression for tumours displaying higher stromal PN expression rates. However, the trends were opposite for the higher stromal values and the patients with high epithelial expression levels denoted the group with the worst prognosis, while higher epithelial values in patients with lower stromal expression levels denoted the group with the best prognosis, suggesting that PN epithelial/stromal interactions play a crucial role in breast carcinogenesis, most likely due to functional cross-talk between the two compartments. On the basis of PN expression in both compartments, we defined 4 subgroups of patients with different mortality rates with the group of patients characterized by positive epithelial and low stromal PN expression cells showing the lowest mortality risk as opposed to the groups of patients identified by a high PN expression in both cell compartments or those identified by a low or absent PN expression in both cell compartments showing the worst mortality rates. The differences were highly statistically significant and were also retained after multiparametric analysis. Competing risk analysis demonstrated that PN expression patterns characterizing each of previous groups are specifically associated with cancer-specific mortality.
CONCLUSIONS: Although they require further validation through larger studies, our findings suggest that the patterns of expression of PN in both compartments can allow for the development of IHC "signatures" that maintain a strong independent predictive value of both all causes and, namely, of cancer-specific mortality.

Li XD, Chen SL, Dong P, et al.
Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy.
Sci Rep. 2016; 6:20894 [PubMed] Free Access to Full Article Related Publications
RNF2 (ring finger protein 2) is frequently overexpressed in several types of human cancer, but the status of RNF2 amplification and expression in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance is unclear. In this study, immunohistochemical analysis and fluorescence in situ hybridization (FISH) were used to examine the expression and amplification of RNF2 in 184 UCB patients after radical cystectomy. Overexpression of RNF2 was observed in 44.0% of UCBs and was found to significantly associate with shortened overall and cancer-specific survival (P < 0.001). In different subsets of UCBs, RNF2 overexpression was also identified as a prognostic indicator in patients with pT1, pT2, pN(-), and/or negative surgical margins (P < 0.05). Importantly, RNF2 overexpression together with pT status and surgical margin status provided significant independent prognostic parameters in multivariate analysis (P < 0.01). FISH results showed amplification of RNF2 in 8/79 (10.1%) of informative UCB cases. Additionally, RNF2 overexpression was significantly associated with RNF2 gene amplification (P = 0.004) and cell proliferation (P = 0.003). These findings suggested that overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for UCB patients who undergo radical cystectomy.

Kim SH, Ezhilarasan R, Phillips E, et al.
Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner.
Cancer Cell. 2016; 29(2):201-13 [PubMed] Free Access to Full Article Related Publications
Activation of nuclear factor κB (NF-κB) induces mesenchymal (MES) transdifferentiation and radioresistance in glioma stem cells (GSCs), but molecular mechanisms for NF-κB activation in GSCs are currently unknown. Here, we report that mixed lineage kinase 4 (MLK4) is overexpressed in MES but not proneural (PN) GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radioresistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-κB regulator IKKα, leading to activation of NF-κB signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-κB signaling and a potential molecular target for the MES subtype of glioblastomas.

Cini G, Mezzavilla M, Della Puppa L, et al.
Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy.
BMC Med Genet. 2016; 17:11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions. In some populations, especially if relatively isolated, a few number of recurrent mutations is reported, sometimes caused by founder effect.
METHODS: BRCA1 and BRCA2 screening for mutations was carried out on 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing. Haplotype analysis was performed on the probands carrying recurrent mutations and their relatives, using two sets of microsatellite markers covering the BRCA1 (D17S588, D17S806, D17S902, D17S1325, D17S855, D17S1328, D17S800, and D17S250) and BRCA2 (D13S220, D13S267, D13S171, D13S1701, D13S1698, D13S260, D13S290, D13S1246) loci. The DMLE + 2.2 software was used to estimate the age of BRCA1 c.676delT and BRCA2 c.7806-2A > G. A multiplex PCR and two different primer extension assays were optimized and used for genotyping the recurrent mutations of the two genes.
RESULTS: In the time frame of almost 20 years of genetic testing, we have found that five BRCA1 and three BRCA2 mutations are recurrent in a substantial subset of carriers from North-East Italy and neighboring Istria, where they represent more than 50 % of all mutations. Microsatellite analyses identified a common haplotype of different length for each mutation. Age estimation of BRCA1 c.676delT and BRCA2 c.7806-2A > G mutations revealed that they arose in the Friuli Venezia Giulia area about 86 and 94 generations ago, respectively. Suggestion of an association between BRCA2 c.7806-2A > G and risk of breast cancer in males has emerged. Finally, we developed a simple and efficient pre-screening test, performing an in-house primer extension SNaPshot® assay for the rapid identification of the eight recurrent mutations.
CONCLUSIONS: Proofs of common ancestry has been obtained for the eight recurrent mutations. The observed genotype-phenotype correlation and the proposed rapid mutation detection strategy could improve the clinical management of breast and ovarian patients in North-East of Italy and neighboring geographic areas.

Chen J, Wei Y, Feng Q, et al.
Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway.
Int J Oncol. 2016; 48(4):1628-38 [PubMed] Related Publications
Ribosomal protein S15A (RPS15A), which has been identified as a highly conserved 40S ribosomal protein, is essential for cell survival and proliferation. The present study evaluated the functional role of RPS15A in colorectal cancer (CRC), and our investigation found that RPS15A was highly expressed in a cohort of human CRC. High RPS15A expression was associated with older age (P=0.035), not receiving preoperative neoadjuvant treatment (P=0.048), higher primary pN stage (P=0.007) and slightly more synchronous distant metastases (P=0.058). The Cox univariate and multivariate hazard regression analysis revealed that higher expression of RPS15A led to a reduction of overall survival rate in CRC, indicating that enhanced RPS15A expression functions as an independent risk factor for the prognosis of CRC patients (P<0.001). Cell based analysis showed that RPS15A was widely expressed in human CRC cell lines. Knockdown of RPS15A significantly suppressed cell proliferation and colony formation in HCT116 and DLD-1 cells, and induced cell cycle arrest at G0/G1 phase. Genechip analysis suggested that knockdown of RPS15A might affect the p53 signaling pathway. Further study indicated that RPS15A knockdown upregulated p53 and p21 expression whereas downregulated CDK1 expression. In summary, the present study identified RPS15A as a novel univariate prognostic factor predicting a poor outcome in CRC patients. The RPS15A overexpression induced by malignant transformation of CRC might function through the p53 signaling pathway.

Sahnane N, Bernasconi B, Carnevali I, et al.
Disruption of the APC gene by t(5;7) translocation in a Turcot family.
Cancer Genet. 2016; 209(3):107-11 [PubMed] Related Publications
Turcot syndrome (TS) refers to the combination of colorectal polyps and primary tumours of the central nervous system. TS is a heterogeneous genetic condition due to APC and/or mismatch repair germline mutations. When APC is involved the vast majority of mutations are truncating, but in approximately 20%-30% of patients with familial polyposis no germline mutation can be found. A 30-year-old Caucasian woman with a positive pedigree for TS was referred to our Genetic Counselling Service. She was negative for APC and MUTYH but showed a reciprocal balanced translocation t(5;7)(q22;p15) at chromosome analysis. FISH analysis using specific BAC probes demonstrated that 5q22 breakpoint disrupted the APC gene. Transcript analysis by MLPA and digital PCR revealed that the cytogenetic rearrangement involving the 3' end of the APC gene caused a defective expression of a truncated transcript. This result allowed cytogenetic analysis to be offered to all the other family members and segregation analysis clearly demonstrated that all the carriers were affected, whereas non-carriers did not have the polyposis. A cytogenetic approach permitted the identification of the mutation-causing disease in this family, and the segregation analysis together with the transcript study supported the pathogenetic role of this mutation. Karyotype analysis was used as a predictive test in all members of this family. This family suggests that clinically positive TS and FAP cases, which test negative with standard molecular analysis, could be easily and cost-effectively resolved by a classical and molecular cytogenetic approach.

Garziera M, Catamo E, Crovella S, et al.
Association of the HLA-G 3'UTR polymorphisms with colorectal cancer in Italy: a first insight.
Int J Immunogenet. 2016; 43(1):32-9 [PubMed] Related Publications
This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3'UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a 'protective' role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF = 0.1%) and +3092 G/T (EUR MAF = 0%). This is the first study showing associations between different polymorphisms in the HLA-G 3'UTR and colorectal cancer susceptibility.

Xue H, Gao X, Xu S, et al.
MicroRNA-Let-7f reduces the vasculogenic mimicry of human glioma cells by regulating periostin-dependent migration.
Oncol Rep. 2016; 35(3):1771-7 [PubMed] Related Publications
The present study was the first to examine the effect of microRNA-Let-7f (miR-Let-7f) inhibiting vasculogenic mimicry (VM) of human glioma cells. The postoperative survival time was significantly poor in VM-positive glioma patients compared with those without VM. Thus, it is reasonable to postulate that miR-Let-7f functions as a potent tumor suppressor by inhibiting glioma VM. However, the molecular mechanisms involved remain poorly clarified. Our preliminary studies revealed that miR-Let-7f suppressed VM by disturbing periostin (POSTN)-induced migration of glioma cells. Our results clearly demonstrated that inhibiting the pro-migratory function of POSTN by the overexpression of miR-Let-7f significantly reduced the formation of VM. Our findings suggest that miR-Let-7f may serve as a potential complementary therapeutic target in the anti‑angiogenesis treatment of gliomas via suppressing VM.

Kim SA, Inamura K, Yamauchi M, et al.
Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis.
Br J Cancer. 2016; 114(2):199-206 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Loss of CDH1 (E-cadherin) expression in cancer cells may promote cell migration and invasion. Therefore, we hypothesised that loss of CDH1 expression in colorectal carcinoma might be associated with aggressive features and clinical outcome.
METHODS: Utilising molecular pathological epidemiology database of 689 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed tumour CDH1 expression by immunohistochemistry. Multivariate logistic regression analysis was conducted to assess association of CDH1 loss with tumour growth pattern (expansile-intermediate vs infiltrative) and lymph node metastasis and distant metastasis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and PIK3CA, BRAF and KRAS mutations. Mortality according to CDH1 status was assessed using Cox proportional hazards model.
RESULTS: Loss of tumour CDH1 expression was observed in 356 cases (52%), and associated with infiltrative tumour growth pattern (odds ratio (OR), 2.02; 95% confidence interval (CI), 1.23-3.34; P=0.006) and higher pN stage (OR, 1.73; 95% CI, 1.23-2.43; P=0.001). Tumour CDH1 expression was not significantly associated with distant metastasis or prognosis.
CONCLUSIONS: Loss of CDH1 expression in colorectal cancer is associated with infiltrative tumour growth pattern and lymph node metastasis.

Chen M, Zheng SH, Liu Y, et al.
Periostin activates pathways involved in epithelial-mesenchymal transition in adamantinomatous craniopharyngioma.
J Neurol Sci. 2016; 360:49-54 [PubMed] Related Publications
Periostin (POSTN) is an extracellular matrix protein (ECM) critical for epithelial-mesenchymal transitions (EMT) in several kinds of tumor cells. Previous studies have indicated that EMT exists in craniopharyngioma (CP), and expression of POSTN is a significant factor in the prognosis of CP. However, it has never been explored whether POSTN exists in CP, or how it activates CP's EMT. The expression of POSTN was examined in adamantinomatous craniopharyngioma (ACP) primary cells and tissues by immunohistochemistry, PCR and Western blot, respectively. The effects and mechanisms of POSTN on ACP cells' EMT were also analyzed. It was found that POSTN expression increased in ACP-associated fibroblasts. Overexpressed POSTN significantly elevated the EMT of ACP cells by regulating the expression of associated genes. More importantly, our further study revealed that the upregulated POSTN activated Akt signaling pathway to regulate the EMT. This study showed that POSTN is responsible for the EMT of ACP cells, and POSTN might be a potential molecular therapeutic target for ACP treatment in future.

Liao Y, Lv G, Wang B, et al.
Imatinib promotes apoptosis of giant cell tumor cells by targeting microRNA-30a-mediated runt-related transcription factor 2.
Mol Med Rep. 2016; 13(2):1739-45 [PubMed] Related Publications
Giant cell tumor (GCT) is an aggressive type of bone tumor consisting of multinucleated osteoclast-like giant cells. Imatinib is a selective inhibitor for certain type III tyrosine kinase receptor family members with a variety of beneficial effects. The purpose of the present study was to determine the therapeutic potential and underlying mechanism of imatinib against GCT. In the present study, cell viability and apoptosis in GCT were analyzed using the MTT assay, flow cytometry and DAPI staining assay. Caspase-3 and -9 activity in GCT cells were analyzed with colorimetric assay kits. In addition, the expression levels of runt-related transcription factor 2 (RunX2) protein and microRNA-30a (miR-30a) in GCT cells were detected using western blotting and quantitative polymerase chain reaction, respectively. Results from the present study demonstrated that imatinib treatment inhibited cell viability, increased cell apoptosis, and significantly promoted caspase-3 and -9 activity in GCT. In addition, imatinib treatment decreased the RunX2 protein expression level. Notably, imatinib was demonstrated to increase miR-30a expression. However, upregulation of miR-30a expression reduced the RunX2 protein expression level, and downregulation of miR-30a expression reversed the anticancer effect of imatinib on GCT, increasing the expression level of RunX2 protein in GCT. The results of the present study indicate that imatinib promotes apoptosis of GCT cells by targeting the miR-30a-mediated RunX2 signaling pathway.

Shi YJ, Tsang JY, Ni YB, et al.
FGFR1 is an adverse outcome indicator for luminal A breast cancers.
Oncotarget. 2016; 7(4):5063-73 [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor receptor 1 (FGFR1) has been suggested to be the candidate gene for 8p11-12 amplification in breast cancer and its therapeutic/ prognostic value is explored. Most previous studies focused on FGFR1 gene amplification, which may not necessarily lead to protein expression. Therefore, analysis of protein level may have more clinical relevance. We evaluated FGFR1 expression in a large cohort of breast cancer by immunohistochemistry, correlated with the tumor clinic-pathologic features, biomarkers expression, and patient's survival. FGFR1 expression was associated mainly with luminal cancers, particularly luminal B subtype (23.5%; p < 0.001), and it also showed adverse prognostic impact on luminal A cancers. FGFR1 expression was associated with higher pN (p = 0.023), pT (p = 0.003) stages, lymphovascular invasion (p = 0.010), p-cadherin (p = 0.028), synaptophysin (p = 0.009) and SOX2 expression (p = 0.034) in luminal A cancers. FGFR1 expressing luminal A cancers showed a similar outcome as luminal B cancers. Multivariate Cox regression analysis demonstrated FGFR1 positive luminal A cancers to be an independently poor prognosticator for disease free survival in luminal cancers (hazard ratio = 3.341, p = 0.008). Thus FGFR1 could be useful in identifying the aggressive cases amongst heterogeneous luminal A cancers. Given the relevance of FGFR pathway in treatment resistance in luminal cancers, FGFR1 could be an important tumor biomarker and adverse prognostic factor potentially exploitable in the clinical management of luminal cancers.

Sengupta D, Byrum SD, Avaritt NL, et al.
Quantitative Histone Mass Spectrometry Identifies Elevated Histone H3 Lysine 27 (Lys27) Trimethylation in Melanoma.
Mol Cell Proteomics. 2016; 15(3):765-75 [PubMed] Free Access to Full Article Related Publications
Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys(27) trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications.

Jiang D, Zheng X, Shan W, Shan Y
The overexpression of miR-30a affects cell proliferation of chondrosarcoma via targeting Runx2.
Tumour Biol. 2016; 37(5):5933-40 [PubMed] Related Publications
MicroRNAs (miRNAs) are emerging as important epigenetic modulators of multiple target genes, leading to abnormal cellular signaling involving cellular proliferation in cancers. Aberrant miRNA expression has been observed in human chondrosarcoma (CS). The purpose of the present study was to evaluate the expression and molecular mechanisms of Runx2 and miR-30a in human CS tissues and CS cell lines JJ012, SW1353, and L3252. In the present study, we found that the expression of miR-30a was markedly downregulated in CS cell lines and human CS tissues, compared to matched non-tumor-associated tissues. Furthermore, miR-30a expression was inversely proportional to that of Runx2 messenger RNA (mRNA) and protein. Upregulation of miR-30a dramatically reduced the proliferation, colony formation, and cell cycle-related proteins of CS cells. Flow cytometry analysis showed that ectopic expression of miR-30a significantly decreased the percentage of S phase cells and increased the percentage of G1/G0 phase cells. Luciferase reporter assays confirmed that miR-30a binding to the 3'-untranslated region (3'-UTR) region of Runx2 inhibited the expression of Runx2 in cancer cells. Taken together, our results suggest that miR-30a plays an important role to inhibit the proliferation of CS cells and presents a novel mechanism for direct miRNA-mediated suppression of Runx2 in CS. Thus, miR-30a/Runx2 may have an important role in treatment of CS patients.

Kastrinos F, Ojha RP, Leenen C, et al.
Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.
J Natl Cancer Inst. 2016; 108(2) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers.
METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided.
RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%.
CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.

Zong JC, Wang X, Zhou X, et al.
Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice.
Oncol Rep. 2016; 35(2):739-48 [PubMed] Related Publications
Breast cancer metastasizes to the bone in a majority of patients with advanced disease resulting in bone destruction. The underlying mechanisms are complex, and both processes are controlled by an interaction between locally and systemically derived signals. Clinically, breast cancer patients with depression have a higher risk of bone metastasis, yet the etiology and mechanisms are yet to be elucidated. MDA‑MB‑231 breast cancer cells were used to establish a bone metastasis model by using intracardiac injection in nude mice. Chronic mild stress (CMS) was chosen as a model of depression in mice before and after inoculation of the cells. Knockdown of the RUNX‑2 gene was performed by transfection of the cells with shRNA silencing vectors against human RUNX‑2. A co‑culture system was used to test the effect of the MDA‑MB‑231 cells on osteoclasts and osteoblasts. RT‑PCR and western blotting were used to test gene and protein expression, respectively. We confirmed that depression induced bone metastasis by promoting osteoclast activity while inhibiting osteoblast differentiation. Free serotonin led to an increase in the expression of RUNX2 in breast cancer cells (MDA‑MB‑231), which directly inhibited osteoblast differentiation and stimulated osteoclast differentiation by the PTHrP/RANKL pathway, which caused bone destruction and formed osteolytic bone lesions. Additionally, the interaction between depression and breast cancer cells was interrupted by LP533401 or RUNX2 knockdown. In conclusion, depression promotes breast cancer bone metastasis partly through increasing levels of gut‑derived serotonin. Activation of RUNX2 in breast cancer cells by circulating serotonin appears to dissociate coupling between osteoblasts and osteoclasts, suggesting that the suppression of gut‑derived serotonin decreases the rate of breast cancer bone metastasis induced by depression.

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