Au/PANI@PtCu-based electrochemical immunosensor for ultrasensitive determination of pro-gastrin-releasing peptide.

An ultrasensitive sandwich-type electrochemical immunosensor for pro-gastrin-releasing peptide (ProGRP) detection was constructed based on PtCu nanodendrites functionalized Au/polyaniline nanospheres (Au/PANI@PtCu). The prepared Au/PANI@PtCu nanocomposites not only possessed excellent electro-catalytic activity of H2O2 reduction due to the synergistic effect between the Au/PANI and PtCu NDs but also provided large specific surface area for detection of antibodies (Ab2) immobilization. In addition, Au nanoparticles encapsulated multi-wall carbon nanotubes (AuNPs@MWCNTs) were also applied to modify the glassy carbon electrode interface for loading numerous capture antibodies (Ab1). In the presence of target ProGRP, a sandwich-type electrochemical immunosensor showed a strong current response from the electro-catalysis of Au/PANI@PtCu toward H2O2 reduction. Benefiting from the exceptional electro-catalytic performance of Au/PANI@PtCu and the high conductivity of AuNPs@MWCNTs, the sandwich-type immunoassay exhibited remarkable sensitivity in detection. The linear range extended from 100 fg/mL to 10 ng/mL, while achieving an impressively low limit of detection of 77.62 fg/mL.

LncRNA AC142119.1 facilitates the progression of neuroblastoma by epigenetically initiating the transcription of MYCN.

BACKGROUND: Oncogene MYCN is closely related with malignant progression and poor prognosis of neuroblastoma (NB). Recently, long non-coding RNAs (lncRNAs) have been recognized as crucial regulators in various cancers. However, whether lncRNAs contribute to the overexpression of MYCN in NB is unclear. METHODS: Microarray analysis were applied to analyze the differentially expressed lncRNAs between MYCN-amplified and MYCN-non-amplified NB cell lines. Bioinformatic analyses were utilized to identify lncRNAs nearby MYCN locus. qRT-PCR was used to detect the expression level of lncRNA AC142119.1 in NB cell lines and tissues. Gain- and loss-of-function assays were conducted to investigate the biological effect of AC142119.1 in NB. Fluorescence in situ hybridization, RNA pull-down, RNA immunoprecipitation, mass spectrometry, RNA electrophoretic mobility shift, chromatin immunoprecipitation and chromatin isolation by RNA purification assays were performed to validate the interaction between AC142119.1 and WDR5 protein as well as MYCN promoter. RESULTS: AC142119.1 was significantly elevated in NB tissues with MYCN amplification, advanced INSS stage and high risk, and associated with poor survival of NB patients. Moreover, enforced expression of AC142119.1 reinforced the proliferation of NB cells in vitro and in vivo. Additionally, AC142119.1 specifically recruited WDR5 protein to interact with MYCN promoter, further initiating the transcription of MYCN and accelerating NB progression. CONCLUSIONS: We identified a novel lncRNA AC142119.1, which promoted the progression of NB through epigenetically initiating the transcription of MYCN via interacting with both WDR5 protein and the promoter of MYCN, indicating that AC142119.1 might be a potential diagnostic biomarker and therapeutic target for NB.

[Corrigendum] PLCε knockdown enhances the radiosensitivity of castration­resistant prostate cancer via the AR/PARP1/DNA­PKcs axis.

Subsequently to the publication of this paper, an interested reader drew to the authors' attention that western blots featured in Figs. 4B and 5G (representing the 'AR' experiments in both cases) appeared to be the same, albeit that the bands were flipped vertically in Fig. 5G relative to Fig. 4B. The authors have re­examined their data and realized that Fig. 5 was assembled incorrectly. The results from all the originally performed experiments were presented to the Editorial Office for our perusal. The revised version of Fig. 5, containing the correct data for the 'AR' experiment in Fig. 5G, is shown on the next page. The authors regret the inadvertent error that was made during the preparation of Fig. 5, and confirm that this error did not seriously affect the conclusions reported in the paper. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologise to the readership for any inconvenience caused. [Oncology Reports 43: 1397­1412, 2020; DOI: 10.3892/or.2020.7520].

Matrine induces autophagy in human neuroblastoma cells via blocking the AKT-mTOR pathway.

Neuroblastoma (NB) is one of the most common malignant solid tumors in children. Despite significant advances in the treatment strategy, the long-term survival rate of NB patients is only 50%. Developing new agents for NB patients deserves attention. Recent research indicates that matrine, a natural quinolizidine alkaloid component extracted from the traditional Chinese medicine Sophora root, is widely used for various diseases, including antitumor effects against a variety of cancers. However, the effect of matrine on NB is unknown. Herein, we found that matrine exerted antiproliferative activity in human NB cells in dose- and time-dependent manner. Matrine triggered autophagy in NB cells by blocking the AKT-mTOR signaling pathway and suppressing the phosphorylation of AKT and mTOR. 3-Methyladenine (3-MA), a PI3K inhibitor, protected against matrine-induced inhibition of cell proliferation, further supporting that the antitumor activity of matrine was at least partly autophagy-dependent. In vivo, matrine reduced tumor growth of SK-N-DZ cells in a dose-dependent manner. Matrine treatment significantly declined the phosphorylation of AKT and mTOR and enhanced the LC3 II/GAPDH ratio in NB xenografts. Altogether, our work uncovered the molecular mechanism underlying matrine-induced autophagy in NB and provided implications for matrine as a potential therapeutic agent against NB.

[Corrigendum] HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.

Following the publication of the above article, an interested reader drew to the authors' attention that the western blotting data shown in Figs. 2F and 5E were strikingly similar, even though they were intended to show the results from differently performed experiments; furthermore, the migration assay images shown for the 24 h 'Blank' and 'Vector' experiments in Fig. 3C were apparently the same. The authors have consulted their original data, and realized that the errors in the presentation of these figures arose inadvertently as a consequence of selecting the wrong images for the 24 h 'Blank' experiement in Fig. 3C and the western blot for the AR / Nucleus experiment in Fig. 5E. The revised versions of Figs. 3 and 5 are shown on the next two pages. All the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. The authors regret that these errors were included in the paper, and also apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 2115­2124, 2019; DOI: 10.3892/mmr.2019.9841].

Prognostic impact of tumor size on patients with neuroblastoma in a SEER-based study.

OBJECTIVE: The prognostic value of tumor size in neuroblastoma (NB) patients has not been fully evaluated. Our purpose is to elucidate the prognostic significance of tumor size in surgery performed on neuroblastoma patients. METHODS: Neuroblastoma patients diagnosed from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results Program (SEER) for the study. Univariate and multivariate Cox proportional hazard regression models were used to identify risk factors and the independent prognostic influences of tumor size on NB patients. Overall survival (OS) was analyzed through univariate Cox regression analysis. To determine the optimal cutoff value of tumor size, we first divided the cohort into three groups (≤5 cm, 5-10 cm, >10 cm). Subsequently, the patients were divided into two groups repeatedly, with tumor size at 1 cm intervals. The cutoff value that maximized prognostic outcome difference was selected. Furthermore, we performed the Kaplan-Meier methods to visually present differences in prognosis between the optimal tumor size cutoff value in different subgroups. RESULTS: A total of 591 NB patients who met the inclusion criteria were selected from the SEER database in this study. Cox analysis showed that age >1 year (HR = 2.42, p < 0.0001), originate from adrenal site (HR = 1.7, p = 0.014), distant stage (HR = 6.4, p < 0.0001), undifferentiated grade (HR = 1.94, p = 0.002), and large tumor size (HR = 1.5, p < 0.0001) independently predicted poor prognosis. For tumor size, there were significant differences in tumor size distribution in different ages, tumor grade, disease stage, and primary site subgroup but not in sex, race, and histology subgroup. Furthermore, both univariate (HR = 4.96, 95% CI 2.31-10.63, p < 0.0001) and multivariable analysis (HR = 2.8, 95% CI 1.29-6.08, p < 0.0001) indicated the optimal cutoff value of tumor size was 4 cm for overall survival of NB patients. Using a 4 cm of tumor size cutoff in subgroups, we found that it can identify poor prognosis patients whatever their age or primary site. Interestingly, tumor size of 4 cm cutoff can only identify unfavorable NB patients with diagnosis at distant-stage disease, or differentiated grade tumor, but not with regional and local or undifferentiated tumor. CONCLUSIONS: Tumor size is first to be recognized as a key prognostic factor of neuroblastoma patients and a cutoff value >4 cm might predict poor prognosis, which should be included in the evaluation of prognostic factors for NB.

Panobinostat reverses HepaCAM gene expression and suppresses proliferation by increasing histone acetylation in prostate cancer.

Increased expression of histone deacetylases (HDACs) affiliated to the epigenetic regulation is common aberration in prostate cancer (PCa). We have confirmed that hepatocyte cell adhesion molecule (hepaCAM), acting as a tumor suppressor gene, is rarely expressed in PCa previously, However, the mechanisms of which is still unknown. The level of histone acetylation reportedly may involve anti-oncogene transcription and expression. In this study, we investigated the effect of panobinostat, the broad-spectrum histone deacetylases inhibitor, on PCa LNCaP and DU145 cell growth, and observed re-expression of hepaCAM when treated with panobinostat. We demonstrated that intranuclear acetylation of lys9 of histone H3 (Ac-H3K9) were increased, while that of both mRNA and protein of HDAC1, HDAC3, and HDAC4 were decreased when the treating concentration of panobinostat increased. We confirmed the relationship between histone acetylation and the expression of hepaCAM and AR in prostate cancer tissues. We also confirmed that panobinostat could overcome the resistance for androgen deprivation therapy (ADT). Further, we combined panobinostat with Ad-hepaCAM, which resulted in significantly increased antitumor activity and significant attenuation of the proliferation-associated genes CCND1 and PCNA compared to each single treatment. In conclusion, panobinostat may enhance the acetylation of lys9 of histone 3 and reverse the hepaCAM expression through its inhibitory effect on HDACs activity in PCa LNCaP and DU145 cells; Ad-hepaCAM combined with panobinostat may synergistically inhibit the growth of LNCaP and DU145 cells, via a potential mechanism associated with the down-regulation of the expression of CCND1 and PCNA. These findings suggest that this therapeutic strategy should be further developed in clinical trials.

Room Temperature Processed Double Electron Transport Layers for Efficient Perovskite Solar Cells.

Zinc Oxide (ZnO) has been regarded as a promising electron transport layer (ETL) in perovskite solar cells (PSCs) owing to its high electron mobility. However, the acid-nonresistance of ZnO could destroy organic-inorganic hybrid halide perovskite such as methylammonium lead triiodide (MAPbI3) in PSCs, resulting in poor power conversion efficiency (PCE). It is demonstrated in this work that Nb2O5/ZnO films were deposited at room temperature with RF magnetron sputtering and were successfully used as double electron transport layers (DETL) in PSCs due to the energy band matching between Nb2O5 and MAPbI3 as well as ZnO. In addition, the insertion of Nb2O5 between ZnO and MAPbI3 facilitated the stability of the perovskite film. A systematic investigation of the ZnO deposition time on the PCE has been carried out. A deposition time of five minutes achieved a ZnO layer in the PSCs with the highest power conversion efficiency of up to 13.8%. This excellent photovoltaic property was caused by the excellent light absorption property of the high-quality perovskite film and a fast electron extraction at the perovskite/DETL interface.

Long noncoding RNA HOTAIR regulates the invasion and metastasis of prostate cancer by targeting hepaCAM.

BACKGROUND: The role of HOX transcript antisense RNA (HOTAIR) has been proven to be important in tumorigenesis. However, how this molecule promotes metastasis and invasion in PCa is still unclear. METHODS: The relationship between HOTAIR and hepatocellular adhesion molecule (hepaCAM) in PCa was identified by immunohistochemistry, immunofluorescence, plasmid transfection, quantitative real-time PCR and immunoblotting. The regulatory effects of HOTAIR on hepaCAM and MAPK signalling and their key roles in PCa metastasis were investigated in vitro. RESULTS: The expression of HOTAIR was inversely correlated with hepaCAM in the blood and tissue of PCa patients. Here, hepaCAM was identified as a novel target gene of HOTAIR and was critical for the invasiveness of PCa. HOTAIR recruited PRC2 to the hepaCAM promoter, resulting in high levels of H3K27me3 and the absence of hepaCAM with an abnormally activated MAPK pathway. Both HOTAIR depletion and EZH2 inhibition could induce hepaCAM re-expression with inhibitory MAPK signalling and decrease the invasive and metastatic capabilities of PCa cells. CONCLUSIONS: This study demonstrates that HOTAIR promotes invasion and metastasis of PCa by decreasing the inhibitory effect of hepaCAM on MAPK signalling. Therefore, the HOTAIR/hepaCAM/MAPK axis may provide a new avenue towards therapeutic strategies and prognostic indicators for advanced prostate cancer.

PLCε knockdown enhances the radiosensitivity of castration­resistant prostate cancer via the AR/PARP1/DNA­PKcs axis.

Radiotherapy (RT) has been used as a therapeutic option for treatment of prostate cancer (PCa) for a number of years; however, patients frequently develop RT resistance, particularly in castration­resistant PCa (CRPC), although the underlying mechanisms remain unknown. Understanding the underlying mechanism of RT resistance in CRPC may potentially highlight novel targets to improve therapeutic options for patients with PCa. In the present study, the expression levels of phospholipase Cε (PLCε), androgen receptor (AR) and DNA­dependent protein kinase catalytic subunit (PKcs) were examined in PCa tissue samples and PCa cells, and the effects of PLCε knockdown on AR and DNA damage repair (DDR)­related molecules were determined. The association between PLCε, AR and Poly (ADP­ribose) polymerase 1 (PARP1), as well as their respective roles in radiation resistance, were assessed using gene knockdown and pharmaceutical inhibitors or activators. A chromatin immunoprecipitation assay was used to determine the epigenetic regulatory effects of PLCε on PARP1. Animal experiments were performed to assess whether the mechanisms observed in vitro could be replicated in vivo. The expression levels of PLCε, AR and DNA­PKcs were significantly upregulated in PCa, particularly in CRPC. PLCε knockdown reduced the viability and increased apoptosis of cells subjected to radiation. Additionally, PLCε deficiency suppressed DDR progression by downregulating an AR and PARP1 positive feedback loop and the associated downstream molecules following radiation. PLCε depletion also increased the presence of histone H3 lysine 27 trimethylation in the PARP1 promoter region, suggesting increased methylation of the PARP1 gene and thus resulting in reduced expression of PARP1. In vivo, PLCε knockdown significantly potentiated the effects of radiation on tumor growth. Taken together, the results of the present study demonstrated that PLCε knockdown enhanced the radiosensitivity of CRPC by downregulating the AR/PARP1/DNA­PKcs axis.

Perfection of Perovskite Grain Boundary Passivation by Rhodium Incorporation for Efficient and Stable Solar Cells.

Organic cation and halide anion defects are omnipresent in the perovskite films, which will destroy perovskite electronic structure and downgrade the properties of devices. Defect passivation in halide perovskites is crucial to the application of solar cells. Herein, tiny amounts of trivalent rhodium ion incorporation can help the nucleation of perovskite grain and passivate the defects in the grain boundaries, which can improve efficiency and stability of perovskite solar cells. Through first-principle calculations, rhodium ion incorporation into the perovskite structure can induce ordered arrangement and tune bandgap. In experiment, rhodium ion incorporation with perovskite can contribute to preparing larger crystalline and uniform film, reducing trap-state density and enlarging charge carrier lifetime. After optimizing the content of 1% rhodium, the devices achieved an efficiency up to 20.71% without obvious hysteresis, from 19.09% of that pristine perovskite. In addition, the unencapsulated solar cells maintain 92% of its initial efficiency after 500 h in dry air. This work highlights the advantages of trivalent rhodium ion incorporation in the characteristics of perovskite solar cells, which will promote the future industrial application.

PLCε knockdown overcomes drug resistance to androgen receptor antagonist in castration-resistant prostate cancer by suppressing the wnt3a/ß-catenin pathway.

Most prostate cancers (Pcas) develop into castration-resistant prostate cancer (CRPC) after receiving androgen deprivation therapy (ADT). The expression levels of PLCε and wnt3a are increased in Pca and regulate androgen receptor (AR) activity. However, the biological function and mechanisms of PLCε and wnt3a in CRPC remain unknown. In this study, we found that the expression levels of PLCε, wnt3a, and AR were significantly increased in CRPC tissues as well as bicalutamide-resistant-LNCaP and enzalutamide-resistant-LNCaP cells. In addition, PLCε knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and enzalutamide by inhibiting the activity of the wnt3a/ß-catenin/AR signaling axis. Interestingly, the resistance of LNCaP cells docetaxel is related to PLCε but not the wnt3a/ß-catenin pathway. We also found that the combination of PLCε knockdown and enzalutamide treatment synergistically suppressed cell proliferation, tumor growth, and bone metastasis using in vitro and in vivo experiments. Our study revealed that PLCε is involved in the progression of drug-resistance in CRPC and could be a new target for the treatment of CRPC.

HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.

Hepatocyte cell adhesion molecule (HepaCAM) is a tumour suppressor. However, the mechanism of HepaCAM function in prostate cancer (PCa) remains unknown. In the present study, HepaCAM, androgen receptor (AR) and Ran were analysed in 46 PCa tissue samples using immunohistochemistry. Subsequently, the influence of HepaCAM and its cytoplasmic domain on cell proliferation, migration, and invasion, and associated proteins was examined using MTT, wound healing, Transwell and western blotting assays, respectively. Furthermore, nuclear translocation of AR and Ran was analysed using immunofluorescence and Western blot assays. The results demonstrated that HepaCAM expression was reduced in PCa, and there was an association between downregulation of HepaCAM and changes in the distribution of AR and Ran. Furthermore, HepaCAM, specifically the cytoplasmic domain, was involved in cell proliferation, migration and invasion. Nuclear translocation of AR was dependent on HepaCAM and its cytoplasmic domain. Additionally, HepaCAM suppression of the nuclear translocation of AR occurred via Ran. The results suggest that HepaCAM and its cytoplasmic domain suppress the nuclear translocation of AR via Ran in PCa. The cytoplasmic domain of HepaCAM may serve as a novel target for therapy in PCa.

HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues. In addition, HepaCAM negativity was found to be associated with a worse progression­free survival (PFS). Furthermore, the overexpression of HepaCAM induced by transfection with a HepaCAM overexpression vector (Ad­HepaCAM) exerted antitumor effects by decreasing the proliferation, and suppressing the invasion and migration of bicalutamide­resistant (Bica­R) cells and enzalutamide­resistant (Enza­R) cells. Importantly, we found that the antitumor effects of HepaCAM on the resistant cells were associated with the downregulation of Notch signaling. Moreover, we revealed that PF­3084014 (a γ­secretase inhibitor) re­sensitized Enza­R cells to enzalutamide, and sequential dual­resistant (E+D­R) cells to docetaxel. Additionally, the findings of this study demonstrated that the use of PF­3084014 alone exerted potent antitumor effect on the resistant cells in vitro. On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF­3084014 may prove to a promising agent for use in the treatment of refractory PCa.

Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway.

Natural killer cells are the key components in tumor immunity and defects in function are necessary for tumor immune escape. Emerging studies on tumor cell-derived exosomes have shown the biological significance in tumor microenvironment, but the underlying role of exosomes in regulating natural killer cells functions in clear cell renal cell carcinoma patients remains unknown. Firstly, we precisely characterized the phenotype and function of natural killer cells in clear cell renal cell carcinoma patients vs healthy controls. With an inhibitory phenotype, tumor-infiltrating natural killer cells exhibited poor cytotoxic capacity and deficient potential to produce cytokines compared with natural killer cells from tumor margin tissue and non-tumor tissue. Next, we revealed that primary tumor cells trigged natural killer cell dysfunction in an exosome-dependent manner. Interestingly, exosomes from primary tumor cells were preferentially enriched with TGF-ß1 which acted as important mediator of natural killer cell functional deficiency. In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-ß/SMAD signaling pathway, and abrogated by knockdown TGF-ß. Our data indicate that exosomes from clear cell renal cell carcinoma induce natural killer cells dysfunction by regulating the TGF-ß/SMAD pathway to evade innate immune surveillance.

Overexpression of HepaCAM inhibits bladder cancer cell proliferation and viability through the AKT/FoxO pathway.

PURPOSE: HepaCAM, an N-linked glycoprotein that encodes a member of the immunoglobulin superfamily, has been reported to be a tumor suppressor gene that mediates diverse cellular bio-functions. Recent studies have shown that the FoxO transcription factors play a pivotal role during cancer progression. Here, we explored the correlation between HepaCAM and the FoxO family via regulation of the PI3K/AKT pathway. METHODS: HepaCAM and FoxO3 expression were detected by immunohistochemistry staining. We detected the effect of HepaCAM on the proliferation and viability of bladder cancer through AKT signaling by colony formation, the MTT assay and Western blotting. We observed the nuclear translocation of FoxO3 by immunofluorescence staining after expressing HepaCAM. RESULTS: HepaCAM depletion was discovered in bladder cancer tissues compared with adjacent normal tissues, and the decreased level was associated with the degradation of FoxO3. Furthermore, re-expression of HepaCAM significantly disrupted T24 and BIU-87 cell colony formation, as well as reduced p-AKT and p-FoxO protein expression. We found that the combined treatment of HepaCAM-overexpressing adenovirus with the PI3K inhibitor LY294002 enhanced the inhibitory effects on cell proliferation, viability and protein expression. Additionally, overexpressed HepaCAM decreased the activated effect on cell proliferation, viability and protein expression of the AKT activator SC79. Moreover, we observed that HepaCAM induced nuclear translocation of FoxO3. CONCLUSIONS: Our research implicated that HepaCAM may function as a novel therapeutic target that inhibits the proliferation of bladder cancer via the AKT/FoxO pathway.

Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b.

Interleukin 6 (IL-6), a tumor promoting cytokine, has been largely implicated in the development of renal cell carcinoma (RCC). Hepatocyte cell adhesion molecule (hepaCAM) is a novel tumor suppressor, which is lost or down-regulated in many cancer types including RCC. In the present study, we intensively investigated the connection between IL-6 and hepaCAM in RCC. Our analysis of RCC tissues, adjacent tissues and paired serum samples from RCC patients revealed that IL-6 was elevated in patient serum and RCC tissue, whereas hepaCAM was completely lost or significantly down-regulated. Furthermore, we observed an association between IL-6 increase and hepaCAM decrease in RCC tissue samples. In the section of cytological researches, we found in RCC cell lines that IL-6 was a direct upstream regulator of hepaCAM, and that hepaCAM down-regulation was involved in IL-6-driven cell proliferation. We also demonstrated that IL-6-mediated promoter hypermethylation largely accounted for the hepaCAM loss in RCC, and it was STAT3-dependent. Additionally, our data showed that DNMT1 up-regulation induced by IL-6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in RCC cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. Our findings provide a novel signal pathway regulating cell proliferation, potentially representing a therapeutic target for RCC.