KIAA1199 Expression Research Articles

Knockdown of KIAA1199 attenuates growth and metastasis of hepatocellular carcinoma

Accumulating evidence indicates that KIAA1199 plays a vital role in tumor progression. However, the role of KIAA1199 in hepatocellular carcinoma (HCC) still remains unknown. In this study, we found that KIAA1199 was upregulated in human HCC tissues and in highly metastatic HCC cell lines. Furthermore, the expression of KIAA1199 was significantly correlated with tumor size and metastasis in HCC. Knockdown of KIAA1199 inhibited cell proliferation and migration in vitro, and suppressed tumorigenicity and lung metastasis in vivo. In addition, silencing of KIAA1199 induced G1 phase arrest by reducing cyclinD1 expression. Moreover, KIAA1199 knockdown induced apoptosis by activating endoplasmic reticulum (ER) stress, which was based on the upregulation of ER stress markers, activating transcription factor 4 (ATF4) and CAAT/enhancer-binding protein homologous protein (CHOP). In conclusion, our data demonstrated that KIAA1199 knockdown inhibited the growth and metastasis of HCC.

KIAA1199 overexpression is associated with abnormal expression of EMT markers and is a novel independent prognostic biomarker for hepatocellular carcinoma.

PurposeTo determined KIAA1199 expression and investigate its correlation with the clinicopathologic data and prognosis of hepatocellular carcinoma (HCC), as well as markers of epithelial-mesenchymal transition (EMT); N-cadherin, E-cadherin and vimentin.Materials and methodsWestern blot, quantitative real-time PCR, and immunohistochemical staining were used to measure KIAA1199 expression in human HCC specimens. Subsequently, the correlation between KIAA1199 expression and the pathological characteristics of HCC patients was analyzed. Univariate and multivariate analyses were used to explore the risk factors associated with disease-free survival (DFS) and overall survival (OS).ResultsKIAA1199 expression was remarkably increased in hepatocellular carcinoma tissues compared to paracarcinomatous tissues. This phenomenon was accompanied by aberrant expression of EMT-associated markers. In addition, high KIAA1199 expression was associated with severe pathological symptoms, low DFS, and low OS. Results of the multivariate analysis showed that KIAA1199 expression may be an independent predictor of low disease-free survival and OS of HCC patients.ConclusionKIAA1199 overexpression in HCC patients is associated with aberrant expression of EMT-associated markers and severe clinicopathological symptoms, and thus may function as a marker of poor prognosis in HCC.

PCNA-associated factor P15PAF , targeted by FOXM1, predicts poor prognosis in high-grade serous ovarian cancer patients.

Activation of the FOXM1 signaling pathway and the PI3K/AKT/mTOR signaling pathway is associated with poor prognosis in ovarian cancer. In this study, we demonstrated that P15PAF (KIAA0101) was significantly upregulated in high-grade serous ovarian cancer (HGSOC) and that high KIAA0101 expression was associated with poor prognosis. FOXM1 transcriptionally activated KIAA0101 to drive proliferation and metastasis of ovarian cancer cells. KIAA0101 activated the PI3K/AKT/mTOR signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in ovarian cancer cells resulting in cisplatin resistance. Thus, KIAA0101 was closely related to the FOXM1 and PI3K/AKT/mTOR signaling pathways. Collectively, these findings provide insights into the mechanisms of poor prognosis of ovarian cancer and have implications for the development of both predictive and therapeutic biomarkers for the treatment of ovarian cancer.

Screening of cell cycle-related genes regulated by KIAA0101 in gastric cancer

To screen the genes related to cell cycle under regulation by KIAA0101 in gastric cancer. RT-PCR was used to detect the expression level of KIAA0101 gene in gastric cancer tissue and paired adjacent tissues. GO function enrichment analysis and KEGG pathway enrichment analysis were carried out using DAVID database. KEGG was used to map the pathways and the corresponding genes were analyzed. The list of genes associated with the KIAA0101 expression pattern was imported into TCGA cBioPortal to analyze the relationship between the interacting genes and generate a genetic topology map. The candidate genes were screened by RT-PCR. The expression level of KIAA0101 mRNA was significantly higher in cancer tissues than in paired adjacent tissues (1.104 ± 0.379 vs 0.421 ± 0.172; P=0.0179). The system screened genes related with KIAA0101 from 478 tissues by pooled analysis of the expression intensity of all the gene probes. GO function analysis showed that the differential genes were mainly enriched in protein phosphorylation, RNA processing, cell cycle, DNA metabolism, protein transport, acetylation, apoptosis, proteolysis, and redox. The changes in the expression level of KIAA0101 mainly affect the gastric cancer-related pathways including cell cycle, spliceosome, DNA replication, and p53 signal transduction pathway. KEGG pathway maps and gene topology maps showed that the genes related to KIAA0101 (such as BUB1B, MAD2L1, CDC45, CDK1, CCNE1 and CCNB2) were also related to cell cycle. RT-PCR results confirmed significant increments of the expression levels of BUB1B, MAD2L, CDK1, CCNE1, and CCNB2 mRNA in gastric cancer tissues as compared with the paired adjacent gastric tissues (P < 0.05), but CDC45 mRNA did not show significant differential expression in gastric cancer tissues (P > 0.05). KIAA0101 may affect cell cycle by regulating the expression of BUB1B, MAD2L1, CDK1, CCNE1 and CCNB2, and this finding may provide evidence for understanding how KIAA0101 affects cell cycle and for screening of tumor markers and selection of drug targets.

KIAA1199 expression and hyaluronan degradation colocalize in multiple sclerosis lesions

Modification of hyaluronan (HA) accumulation has been shown to play a key role in regulating inflammatory processes linked to the progression of multiple sclerosis (MS). The aim of this study was to characterize the enzymatic activity involved in HA degradation observed within focal demyelinating lesions in the experimental autoimmune encephalomyelitis (EAE) animal model. EAE was induced in 3-month-old female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 33–35 (MOG33–35) peptide. The mice were monitored for 21 days. Formalin-fixed paraffin-embedded tissue from control and EAE mice were labeled with an immunoadhesin against HA, antibodies against KIAA1199 and glial fibrillary acidic protein, a marker for astrocytes. In situ hybridization was conducted using a KIAA1199 nucleic acid probe. In histologic sections of spinal cord from EAE mice, abnormal HA accumulation was observed in the close vicinity of the affected areas, whereas HA was totally degraded within the focal loci of damaged tissue. KIAA1199 immunoreactivity was exclusively associated with focal loci in damaged white columns of the spinal cord. KIAA1199 was mainly expressed by activated astrocytes that invaded damaged tissue. Similar findings were observed in tissue from an MS patient. Here, we show that KIAA1199, a protein that plays a role in a HA degradation pathway independent of the canonical hyaluronidases such as PH20, is specifically expressed in tissue lesions in which HA is degraded. KIAA1199 expression by activated astrocytes may explain the focal HA degradation observed during progression of MS and could represent a possible new therapeutic target.

Expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma

Objective: To investigate the expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma. Methods: A total of 136 cases of primary hepatocellular carcinoma tissues and paired adjacent tissues were collected. Immunohistochemistry and Western blot were used to detect the expression of KIAA1199 in primary hepatocellular carcinoma tissues and paired adjacent tissues. The relationship between KIAA1199 and clinicopathological parameter of primary hepatocellular carcinoma was analyzed. Results: The positive rate of KIAA1199 in primary hepatocellular carcinoma was 82.3% (112/136), which was higher than that in paired para-cancerous tissues (14.7%, 20/136). High expression of KIAA1199 was significantly correlated with age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and microvenous invasion (MVI) (P<0.05), but without gender, drinking alcohol hobby, hepatitis history, family genetic history, tumor location (P>0.05). The Kaplan-Meier survival curves indicated that high KIAA1199 expression was associated with poor survival (P<0.01). In addition, Cox proportional hazards model showed that the expression of KIAA1199 was related to age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and MVI (P<0.05). Conclusion: The expression of KIAA1199 is up-regulated in primary hepatocellular carcinoma, which is significantly correlated with the clinicopathological features and prognosis, high expression of KIAA1199 increased the risk of death in patients with primary hepatocellular carcinoma.

RETRACTED ARTICLE: LncRNA TUG1 promoted KIAA1199 expression via miR-600 to accelerate cell metastasis and epithelial-mesenchymal transition in colorectal cancer

BackgroundLncRNA TUG1 has been reported to be highly expressed in CRC samples and cells and promoted metastasis by affecting EMT, indicating a poor prognosis for colorectal cancer (CRC). In this study, we determined the underlying mechanism for tumor oncogenesis of lncRNA TUG1 in CRC metastasis.MethodsThe expressions of miR-600 and KIAA1199 in 76 CRC patients and CRC cells and CRC metastatic tissues were determined using qRT-PCR. Epithelial-mesenchymal transition (EMT)-related proteins were determined using western blot. CRC cell metastasis was assessed by colony formation, wound healing and transwell assay. Luciferase reporter gene assay was used to confirm miR-600 binding to KIAA1199 3’UTR.ResultsOur data showed that lncRNA TUG1 was upregulated in CRC cells, miR-600 was downregulated in CRC tissues, cell lines and CRC metastatic tissues, and low miR-600 expression predicted a poor clinical prognosis. Overexpression of miR-600 suppressed CRC cell migration/invasion and EMT-related proteins in vitro, inhibited tumor volume and weight, and decreased the number of CRC liver metastasis in vivo. KIAA1199 was upregulated in CRC tissues, and was negatively regulated by miR-600. KIAA1199 overexpression promoted CRC cell migration and invasion, which reversed the inhibition effect of miR-600 mimic on migration and invasion of CRC cells. Moreover, TUG1 negatively regulated miR-600, and inhibition of TUG1 suppressed CRC cell migration and invasion and EMT-related proteins via regulating miR-600.ConclusionOur study proved that TUG1 promoted KIAA1199 expression to accelerate EMT and metastasis of CRC cell through inhibition of miR-600 expression.

KIAA1522 overexpression promotes tumorigenicity and metastasis of esophageal cancer cells through potentiating the ERK activity.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor associated with a poor prognosis, and the molecular mechanisms underlying its formation and progression remain poorly understood. KIAA1522 is upregulated in various tumor tissues, but its function is unknown. Alterations in KIAA1522 expression and its implication in ESCC are currently unclear. In this study, an immunohistochemical analysis of ESCC tissues showed that KIAA1522 was highly expressed in 46% (157/342) of ESCC specimens and that its expression was inversely correlated with the degree of differentiation (P=0.03). Furthermore, small interfering RNA-mediated silencing of KIAA1522 revealed that overexpression of this protein reinforced malignant cell proliferation and anoikis resistance of ESCC cells in vitro. More importantly, KIAA1522 depletion significantly suppressed the growth of ESCC xenograft tumors and lung metastasis of ESCC cells in nude mice. At the molecular level, inhibition of KIAA1522 expression markedly reduced the phosphorylated extracellular signal-regulated kinase (ERK) levels in both suspended and adherent ESCC cells, suggesting that KIAA1522 might promote cell proliferation and survival via the ERK cascade. Taken together, these data suggest that upregulation of KIAA1522 might enhance tumorigenicity and metastasis of ESCC cells through potentiating the ERK activity. Thus, aberrant expression of KIAA1522 plays oncogenic roles in ESCC and might serve as a novel molecular target in ESCC treatment.

KIAA1199 promotes migration and invasion by Wnt/β-catenin pathway and MMPs mediated EMT progression and serves as a poor prognosis marker in gastric cancer.

BackgroundKIAA1199 was upregulated in diverse cancers, but the association of KIAA1199 with gastric cancer (GC), the biological role of KIAA1199 in GC cells and the related molecular mechanisms remain to be elucidated.MethodsKIAA1199 expression was analysed by reverse transcription-polymerase chain reaction assay (RT-PCR) and immunohistochemistry (IHC) in GC patient tissue. The small hairpin RNA (shRNA) was applied for the knockdown of endogenous KIAA1199 in NCI-N87 and AGS cells. MTT, colony formation, scratch wounding migration, transwell chamber migration and invasion assays were employed respectively to investigate the role of KIAA1199 in GC cells. The potential signaling pathway of KIAA1199 induced migration and invasion was detected.ResultsKIAA1199 was upregulated in GC tissue and was an essential independent marker for poor prognosis. Knockdown KIAA1199 suppressed the proliferation, migration and invasion in GC cells. KIAA1199 stimulated the Wnt/β-catenin signaling pathway and the enzymatic activity of matrix metalloproteinase (MMP) family members and thus accelerated the epithelial-to-mesenchymal transition (EMT) progression in GC cells.ConclusionThese findings demonstrated that KIAA1199 was upregulated in GC tissue and associated with worse clinical outcomes in GC, and KIAA1199 acted as an oncogene by promoting migration and invasion through the enhancement of Wnt/β-catenin signaling pathway and MMPs mediated EMT progression in GC cells.

KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer.

BackgroundRecent evidence suggests a critical role of hyaluronan (HA), especially low-molecular-weight HA (LMW-HA), in the aggressive tumor phenotype. Increased expression of KIAA1199, a newly identified protein involved in HA degradation, has been reported in various cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the functional significance of KIAA1199 in PDAC.MethodsUsing siRNA knockdown and forced expression models, we investigated the effects of KIAA1199 expression on malignant behaviors (proliferation, migration, and invasion) of PDAC cells. We also examined the effect of inflammation on the transcriptional regulation of KIAA1199 using a pro-inflammatory cytokine and anti-inflammatory agent.ResultsKnockdown of KIAA1199 expression using siRNA resulted in decreased cell migration and proliferation. On the other hand, forced expression of KIAA1199 using gene transduction significantly enhanced the migration and invasion. Importantly, increased KIAA1199 expression was associated with an increased level of LMW-HA in the conditioned medium. Exposure to a pro-inflammatory cytokine, interleukin-1ß, increased the KIAA1199 transcription and enhanced the migration. In contrast, treatment with NS-398, a cyclooxygenase-2 inhibitor, decreased the KIAA1199 expression and inhibited the migration.ConclusionsThese findings suggest that increased KIAA1199 expression may contribute to the aggressive phenotype partly through increasing the LMW-HA concentration. Our present results also suggest a possible link between inflammation, induced KIAA1199 expression, and enhanced migration during PDAC progression.

Overexpression of KIAA1199: An independent prognostic marker in nonsmall cell lung cancer.

KIAA1199 has been identified as an oncogene in many cancers. Here, we collected 153 cases of nonsmall cell lung cancer (NSCLC) tissues to investigate the relationships between KIAA1199 protein and clinical factors. Immunohistochemistry (IHC) staining was used to detect the expression of KIAA1199. Follow-up included blood analysis, chest X-ray, ultrasound examination, and computed tomography was carried out every 3 months for the first 2 years and at 6-month intervals thereafter during the follow-up period (3 years). Kaplan-Meier survival analysis and Cox analysis were applied to identify the relationship between KIAA1199 and NSCLC. IHC results showed that 76 (49.67%) specimens had strong expression of KIAA1199 protein, with poor differentiation (P = 0.003), higher positive lymph node metastasis (P = 0.037), and higher tumor node metastasis stage (P = 0.016). Using Kaplan-Meier survival analysis, it is found that patients with high KIAA1199 protein expression have poor overall survival (P = 0.004). Cox analysis suggested that the KIAA1199 protein was an independent prognostic marker for NSCLC patients (P = 0.040). Our findings revealed that KIAA1199 protein could be applied in predicting NSCLC patient's outcome.

KIAA1199/CEMIP/HYBID overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma

BackgroundKIAA1199 (also known as CEMIP or HYBID), a newly identified protein involved in hyaluronan degradation, has been suggested to play a critical role in cancer progression. The aim of this study was to investigate the expression and functional significance of KIAA1199 in pancreatic ductal adenocarcinoma (PDAC). MethodsUsing quantitative real-time RT-PCR, we analyzed KIAA1199 mRNA expression in 6 PDAC cell lines and frozen tissues from 14 patients with PDAC. We also used immunohistochemistry to analyze KIAA1199 protein expression in formalin-fixed, paraffin-embedded tissues from 98 patients with PDAC. The KIAA1199 expression pattern was then correlated with clinicopathological variables and patient outcome. The effect of KIAA1199 on migratory ability of PDAC cells was determined by KIAA1199 knockdown with small-interfering RNA (siRNA). ResultsThe KIAA1199 mRNA expression was significantly higher in PDAC tissues than in the corresponding non-tumor tissues (P < 0.0001). Immunohistochemical analysis revealed high expression of KIAA1199 in 26 (26.5%) of 98 PDAC tissues. The overall survival was significantly shorter in patients with high KIAA1199 expression than in patients with low KIAA1199 expression (P = 0.0001). In multivariate analysis, high KIAA1199 expression (P = 0.003) and UICC stage (P = 0.003) were independent factors predicting poor prognosis. Furthermore, the KIAA1199 mRNA expression was higher in most PDAC cell lines and siRNA knockdown of KIAA1199 resulted in decreased migration. ConclusionThese findings suggest that overexpression of KIAA1199 may contribute to increased migration of PDAC cells and predict shorter survival after surgical resection.

KIAA0101, a target gene of miR-429, enhances migration and chemoresistance of epithelial ovarian cancer cells

BackgroundOvarian cancer is a common type of gynecological malignancies, and is the fifth leading cause of cancer-related death in women in the United States. MiR-429 and KIAA0101 have been found to be involved in several human malignancies, respectively. However, the role of miR-429 and KIAA0101, and the correlation between them during development of epithelial ovarian cancer (EOC) remain to be investigated.MethodsThe expression of KIAA0101 in EOC tissues and cells was measured by Quantitative real-time PCR, western blot, and immunochemistry. Cell proliferation assay, colony formation assay, and transwell assay was performed to assess the role of miR-429 and KIAA0101 in regulation of proliferation, migration, and chemoresistance of EOC cells. Luciferase assay was used to test the Wnt/β-catenin signaling activity in response to depletion of KIAA0101 and overexpression of miR-429.ResultsWe found that KIAA0101 was upregulated in metastatic EOC tissues, compared to primary EOC tissues, and KIAA0101 was required for the migration activity and chemoresistance of EOC cells by enhancing Wnt/β-catenin signaling. Furthermore, we revealed KIAA0101 is direct target of miR-429. Similar to knockdown of KIAA0101, overexpression of miR-429 reduced invasion and chemoresistance of EOC cells. Co-transfection of KIAA0101 partially abrogates the inhibitory effects on invasion and chemoresistance in EOC cells.ConclusionsKIAA0101, a target gene of miR-429, was upregulated in the metastatic EOC tissues, and enhanced the migration activity and chemoresistance of EOC cells. Both miR-429 and KIAA0101 may represent the potential therapeutic targets of EOC.

MiR-183 Inhibits UV-Induced DNA Damage Repair in Human Trabecular Meshwork Cells by Targeting of KIAA0101.

PurposeThe purpose of this study was to investigate the mechanisms by which miR-183 may contribute to the phenotypic alterations associated with stress-induced senescence of human trabecular meshwork (HTM) cells.MethodsChanges in gene expression induced by miR-183 in HTM cells were evaluated by gene array analysis, confirmed by quantitative-PCR (Q-PCR), and analyzed by MetaCore pathway analysis. Effects of miR-183 on cell proliferation were assessed by incorporation of bromodeoxyuridine incorporation, and DNA damage by CometAssay after ultraviolet (UV) irradiation in primary HTM cells, and confirmed in human diploid fibroblasts (HDF) and HeLa cells. A plasmid expressing KIAA0101 without its 3′-untranslated region (3′-UTR) was cotransfected with miR-183 to evaluate the role of KIAA0101 on the effects induced by miR-183.ResultsmiR-183 affected the expression of multiple genes involved in cell cycle regulation and DNA damage response in HTM cells. Forced expression of miR-183 in HTM and HDF resulted in a significant decrease in proliferation in primary HTM and HDF cells but not in HeLa cells. In all cell types tested, overexpression of miR-183 resulted in increased DNA damage under UV irradiation. Expression of KIAA0101 lacking the 3′-UTR region partially prevented the effects of miR-183 on cell proliferation and completely reversed the effects on UV-induced DNA damage.ConclusionsOur results suggest that the observed up-regulation of miR-183 after stress-induced senescence in HTM cells may contribute to reinforce cellular senescence by inhibiting cell cycle progression through multiple gene targets and limiting the DNA repair mechanisms through inhibition of KIAA0101.

KIAA1522 is a novel prognostic biomarker in patients with non-small cell lung cancer.

Nowadays, no robust biomarkers have been applied to clinical practice to provide prognostic evaluation of non-small cell lung cancer (NSCLC). This study aims to identify new potential prognostic biomarkers for NSCLC. In the present work, KIAA1522 is screened out from two independent GEO datasets as aberrantly up-regulated gene in NSCLC tissues. We evaluate KIAA1522 expression immunohistochemically in 583 NSCLC tissue samples and paired non-tumor tissues. KIAA1522 displays stronger staining in NSCLC cases than in adjacent normal lung tissues. Importantly, patients with KIAA1522 overexpression had a significantly shorter overall survival compared to those with low expression (P < 0.00001). Multivariate Cox regression analyses show that KIAA1522 is an independent prognostic indicator, even for early-stage NSCLCs (P = 0.00025, HR = 2.317, 95%CI: 1.477–3.635). We also found that high expression of KIAA1522 is a significant risk factor for decreased overall survival of the patients who received platinum-based chemotherapy. Gene set enrichment analysis (GSEA) and functional studies reveal that KIAA1522 is associated with oncogenic KRAS pathways. Taken together, high expression of KIAA1522 can be used as an independent biomarker for predication of poor survival and platinum-resistance of NSCLC patients, and aberrant KIAA1522 might be a new target for the therapy of the disease.

Distinct Expression Pattern of a Deafness Gene, KIAA1199, in a Primate Cochlea.

Deafness is one of the most common types of congenital impairments, and at least half of the cases are caused by hereditary mutations. Mutations of the gene KIAA1199 are associated with progressive hearing loss. Its expression is abundant in human cochlea, but interestingly the spatial expression patterns are different between mouse and rat cochleae; the pattern in humans has not been fully investigated. We performed immunohistochemical analysis of a nonhuman primate, common marmoset (Callithrix jacchus), cochlea with a KIAA1199-specific antibody. In the common marmoset cochlea, KIAA1199 protein expression was more widespread than in rodents, with all epithelial cells, including hair cells, expressing KIAA1199. Our results suggest that the primate pattern of KIAA1199 expression is wider in comparison with rodents and may play an essential role in the maintenance of cochlear epithelial cells.

KIAA0101 is associated with human renal cell carcinoma proliferation and migration induced by erythropoietin.

Erythropoietin (EPO) is a frequently prescribed anti-anemic drug for patients with advanced renal carcinoma. However, recent evidence from clinical studies suggested that EPO accelerated tumor progression and jeopardized the 5-year survival. Herein, we show, starting from the in silico microarray bioinformatics analysis, that activation of Erythropoietin signaling pathway enhanced renal clear carcinoma (RCC) progression. EPO accelerated the proliferative and migratory ability in 786-O and Caki-2 cells. Moreover, comparative proteomics expression profiling suggested that exogenous EPO stimulated RCC progression via up-regulation of KIAA0101 expression. Loss of KIAA0101 impeded the undesirable propensity of EPO in RCC. Finally, low expression of KIAA0101 was associated with the excellent prognosis and prognosticated a higher 5-year survival in human patients with renal carcinoma. Overall, KIAA0101 appears to be a key promoter of RCC malignancy induced by EPO, which provide mechanistic insights into KIAA0101 functions, and pave the road to develop new therapeutics for treatment of cancer-related and chemotherapy-induced anemia in patients with RCC.

Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors.

Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients.

KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis.

IntroductionOur previous proteomic study on fibroblast-like synoviocytes (FLSs) derived from the synovial tissues found that the expression of KIAA1199 was higher in rheumatoid arthritis (RA) patients than in healthy controls. The aim of this study was to examine the biological function of KIAA1199 and evaluate its clinical diagnosis value in RA.MethodsThe over-expression of KIAA1199 was verified by quantitative real-time polymerase chain reaction (qPCR), Immunohistochemistry, Immunofluorescence and enzyme linked immunosorbent assay (ELISA) in inactive and active RA patients and healthy controls. The effect of KIAA1199 expression on FLSs proliferation, angiogenesis and related pathway were analyzed by MTT, cell migration, tube formation, chorioallantoic membrane (CAM) assay, qPCR and western-blotting after KIAA1199 knockdown and over-expression.ResultsThe verification results show the up-regulation of KIAA1199 in RA patients at mRNA and protein level as compared to that in healthy controls. ELISA and receiver operator characteristic (ROC) analysis shows that KIAA1199 concentration in serum, synovial fluid and synovial tissues could be used as dependable biomarkers for the diagnosis of active RA, provided an area under roc curve (AUC) of 0.83, 0.92 and 0.92. Sensitivity and specificity, which were determined by cut-off points, reached 72% 84% and 80% in sensitivity and 80%, 93.3%, 93.3% in specificity, respectively. Moreover, KIAA1199 also enhance the proliferation and angiogenesis of synovial membrane, and KIAA1199/ PLXNB3/ SEMA5A/CTGF axis may be a newly found pathway enhancing cell proliferation and angiogenesis.ConclusionKIAA1199 may be a potential diagnostic biomarker of RA related to angiogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0637-y) contains supplementary material, which is available to authorized users.

NF-κB-induced KIAA1199 promotes survival through EGFR signalling.

Constitutive activation of EGFR- and NF-κB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial–mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-κB activity that transmits pro-survival and invasive signals through EGFR signalling.