RUVBL1 ubiquitination by DTL promotes RUVBL1/2-ß-catenin-mediated transcriptional regulation of NHEJ pathway and enhances radiation resistance in breast cancer.

Radiotherapy effectiveness in breast cancer is limited by radioresistance. Nevertheless, the mechanisms behind radioresistance are not yet fully understood. RUVBL1 and RUVBL2, referred to as RUVBL1/2, are crucial AAA+ ATPases that act as co-chaperones and are connected to cancer. Our research revealed that RUVBL1, also known as pontin/TIP49, is excessively expressed in MMTV-PyMT mouse models undergoing radiotherapy, which is considered a murine spontaneous breast-tumor model. Our findings suggest that RUVBL1 enhances DNA damage repair and radioresistance in breast cancer cells both in vitro and in vivo. Mechanistically, we discovered that DTL, also known as CDT2 or DCAF2, which is a substrate adapter protein of CRL4, promotes the ubiquitination of RUVBL1 and facilitates its binding to RUVBL2 and transcription cofactor ß-catenin. This interaction, in turn, attenuates its binding to acetyltransferase Tat-interacting protein 60 (TIP60), a comodulator of nuclear receptors. Subsequently, ubiquitinated RUVBL1 promotes the transcriptional regulation of RUVBL1/2-ß-catenin on genes associated with the non-homologous end-joining (NHEJ) repair pathway. This process also attenuates TIP60-mediated H4K16 acetylation and the homologous recombination (HR) repair process. Expanding upon the prior study's discoveries, we exhibited that the ubiquitination of RUVBL1 by DTL advances the interosculation of RUVBL1/2-ß-catenin. And, it then regulates the transcription of NHEJ repair pathway protein. Resulting in an elevated resistance of breast cancer cells to radiation therapy. From the aforementioned, it is evident that targeting DTL-RUVBL1/2-ß-catenin provides a potential radiosensitization approach when treating breast cancer.

DDX18 drives tumor immune escape through transcription-activated STAT1 expression in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) resists to current treatments due to its inherent tumor heterogeneity, therapy-resistant cancer stem/initiating cells survival, and immune evasion in the immunosuppressive tumor microenvironment (TME). Here, the results show that clinical PDAC and adjacent tissues undergo distinct chromatin remodeling. Multiple omics analysis revealed DEAD-box RNA helicase 18 (DDX18), a carcinogenic gene with similar H3K4me3 profile, is up-regulated and correlates with poor survival in PDAC patients. We validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter sequence by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1, which results in the up-regulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME. DDX18-STAT1 axis inhibition also affects stemness of cancer cells, epithelial-mesenchymal transition (EMT) and disrupts the immunosuppressive TME simultaneously, producing sustained remissions of aggressive PDAC by synergizing with anti-PD-L1 therapy. Combining DDX18 inhibition with anti-PD-L1 immunochemotherapy to treat PDAC patients will pave a new way for clinical treatment of patients with PDAC. This study found that clinical PDAC and adjacent pancreatic tissues undergo distinct chromatin remodeling featured by the upregulation of DEAD-box RNA helicase 18 (DDX18). We further validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1. DDX18-STAT1 axis enhances the stemness of cancer cells, the upregulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME.

S-allylmercaptocysteine promotes anti-tumor immunity by suppressing PD-L1 expression.

SAMC (S-allylmercaptocysteine) possesses significant anti-tumor effects and is proven to inhibit inflammation in chronic obstructive pulmonary disease. The potential to regulate the immune system of SAMC inspired us to detect whether SAMC can promote anti-tumor immunity. Here we found that SAMC inhibits tumor development and progression by boosting CD8+ T cell and NK cell infiltration and decreasing the frequency of immune suppressing Treg cells in tumor tissue and enhancing the systemic immune function. Mechanistically, we found that SAMC suppresses PD-L1 expression at transcriptional level to increase the activation of anti-tumor cytotoxic T cells. Finally, we proved that SAMC inhibits PD-L1 transcription by suppressing the phosphorylation activation of STAT3. In conclusion, our findings reveal that SAMC is a potent immunity regulator and a potential agent for immune checkpoint inhibition in tumor therapy.

[Retracted] Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer.

Following the publication of this paper, it was drawn to the Editor's attention by concerned readers that several of the cellular images shown in Figs. 6A and 8A, the scratch­wound assay images shown in Fig. 5A, the western blotting data in Figs. 2C and 7A and the Matrigel invasion assays in Fig. 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 36: 204­214, 2015; DOI: 10.3892/ijmm.2015.2217].

[Retracted] Suppression of CUL4A attenuates TGF­ß1­induced epithelial­to­mesenchymal transition in breast cancer cells.

Subsequently to the publication of the above article, and a Corrigendum that was published with the intention of rectifying the issue of overlapping data panels showing cell migration and invasion assay data in Fig. 8 (DOI: 10.3892/mmr.2018.9415; published online on September 24, 2017), it was drawn to the Editors' attention by a concerned reader that certain of the data shown for the epithelial­mesenchymal transition experiments in Fig. 2B, western blotting data in Fig. 6 and scratch­wound assay data shown in Fig. 7A were strikingly similar to data appearing in different form in other articles by different authors at different research institutes, which had already been published elsewhere prior to this paper's submission to International Journal of Molecular Medicine. In addition, several other instances of overlapping data panels were identified in Fig. 8. Owing to the fact that a substantial number of contentious data included in this paper had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 40: 1114­1124, 2017; DOI: 10.3892/ijmm.2017.3118].

Protein modifications throughout the lung cancer proteome unravel the cancer-specific regulation of glycolysis.

Glycolytic reprogramming is a typical feature of cancer. However, the cancer-specific modulation of glycolytic enzymes requires systematic elucidation. Here, we report a range of dysregulated modifications in association with a family of enzymes specifically related to the glycolysis pathway by systematic identification of delta masses at the proteomic scale in human non-small-cell lung cancer. The most significant modification is the delta mass of 79.967 Da at serine 58 (Ser58) of triosephosphate isomerase (TPI), which is confirmed to be phosphorylation. Blocking TPI Ser58 phosphorylation dramatically inhibits glycolysis, cancer growth, and metastasis. The protein kinase PRKACA directly phosphorylates TPI Ser58, thereby enhancing TPI enzymatic activity and glycolysis. The upregulation of TPI Ser58 phosphorylation is detected in various human tumor specimens and correlates with poor survival. Therefore, our study identifies a number of cancer-specific protein modifications spanned on glycolytic enzymes and unravels the significance of TPI Ser58 phosphorylation in glycolysis and lung cancer development.

Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer.

BACKGROUND: DNA damage response plays critical roles in tumor pathogenesis and radiotherapy resistance. Protein phosphorylation is a critical mechanism in regulation of DNA damage response; however, the key mediators for radiosensitivity in gastric cancer still needs further exploration. METHODS: A quick label-free phosphoproteomics using high-resolution mass spectrometry and an open search approach was applied to paired tumor and adjacent tissues from five patients with gastric cancer. The dysregulated phosphoproteins were identified and their associated-pathways analyzed using Gene Set Enrichment Analysis (GSEA). The mostly regulated phosphoproteins and their potential functions were validated by the specific antibodies against the phosphorylation sites. Specific protein phosphorylation was further analyzed by functional and clinical approaches. RESULTS: 832 gastric cancer-associated unique phosphorylated sites were identified, among which 25 were up- and 52 down-regulated. Markedly, the dysregulated phosphoproteins were primarily enriched in DNA-damage-response-associated pathways. Particularly, the phosphorylation of Bcl-2-associated transcription factor 1 (BCLAF1) at Ser290 was significantly upregulated in tumor. The upregulation of BCLAF1 Ser290 phosphorylation (pBCLAF1 (Ser290)) in tumor was confirmed by tissue microarray studies and further indicated in association with poor prognosis of gastric cancer patients. Eliminating the phosphorylation of BCLAF1 at Ser290 suppressed gastric cancer (GC) cell proliferation. Upregulation of pBCLAF1 (Ser290) was found in association with irradiation-induced γ-H2AX expression in the nucleus, leading to an increased DNA damage repair response, and a marked inhibition of irradiation-induced cancer cell apoptosis. CONCLUSIONS: The phosphorylation of BCLAF1 at Ser290 is involved in the regulation of DNA damage response, indicating an important target for the resistance of radiotherapy.

CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation.

Genomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear. Here, we discovered that the CUL4A-DTL ligase complex targeted the DNA-PKcs protein in the NHEJ repair pathway for nuclear degradation. Overexpression of either CUL4A or DTL reduced NHEJ repair efficiency and subsequently increased the accumulation of DSBs. Moreover, we demonstrated that overexpression of either CUL4A or DTL in normal cells led to genomic instability and malignant proliferation. Consistent with the in vitro findings, in human precancerous lesions, CUL4A expression gradually increased with increasing malignant tendency and was negatively correlated with DNA-PKcs and positively correlated with γ-H2AX expression. Collectively, this study provided strong evidence that the CUL4A-DTL axis increases genomic instability and enhances the subsequent malignant transformation of normal cells by inhibiting NHEJ repair. These results also suggested that CUL4A may be a prognostic marker of precancerous lesions and a potential therapeutic target in cancer.

Comprehensive mutanome analysis of Lewis lung cancer reveals immunogenic neoantigens for therapeutic vaccines.

Personalized neoantigen vaccines are capable of eliciting vigorous T-cell responses and have been demonstrated to achieve striking therapeutic effects against cancer. Here we performed comprehensive mutanome analysis of the mouse Lewis lung cancer cells to identify tumor neoantigens followed by prediction of their MHC affinity and immunogenicity. We adopted a strategy that enables us to select neoantigens that were predicted to have high affinity to both MHC I and MHC II. Ten neoantigens were selected to synthesize peptide vaccines and tested in vivo for immunogenicity. Four neoantigen peptide vaccines were found to elicit robust immune reactivity and were further examined for tumor inhibition in mice with xenografted LLC tumors. Two neoantigen peptide vaccines showed significant inhibition on tumor growth and prolonged the survival of tumor-bearing mice. Our studies explored the neoantigen peptide vaccines to treat lung cancer and provide rationale for the optimization of tumor neoantigen selection for therapeutic vaccines.

FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer.

PURPOSE: FAM83D has been proposed to act as an oncoprotein in several types of human cancer. Its role and mode of action in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy are as yet, however, poorly understood. METHODS: FAM83D expression was measured in NSCLC cells and normal lung epithelial cells, as well as in primary NSCLC tissues and corresponding adjacent non-cancerous tissues, using qRT-PCR, Western blotting and immunohistochemistry. FAM83D was stably overexpressed in BEAS2B cells or silenced in A549 and H1299 cells using retroviral or lentiviral vectors. The growth capacity of NSCLC cells was evaluated using MTT and colony formation assays. Epithelial-mesenchymal transition (EMT) was assessed using Western blotting and immunofluorescence. NSCLC cell invasive capacities were assessed using scratch wound healing and Boyden chamber assays. NSCLC cell viability in response to cisplatin treatment was assessed using MTT assays in vitro and a xenograft model in vivo. RESULTS: We found that FAM83D expression levels were significantly elevated in NSCLC cells and tissues, and positively correlated with tumor progression and a poor prognosis. Exogenous FAM83D overexpression promoted, while FAM83D silencing inhibited NSCLC cell proliferation, EMT and invasion. FAM83D silencing also reduced cisplatin resistance. Concordantly, we found that NSCLC patients with a low FAM83D expression benefited most from chemotherapy. Mechanistically, we found that FAM83D activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Pharmacological treatment with either AKT or mTOR inhibitors reverted FAM83D-induced tumorigenic phenotypes. CONCLUSIONS: Our results suggest a role of FAM83D in NSCLC development. In addition, our results indicate that NSCLC patients exhibiting FAM83D overexpression are likely to benefit from AKT and/or mTOR inhibitor treatment.

Carnosic Acid Reverses the Inhibition of ApoE4 on Cell Surface Level of ApoER2 and Reelin Signaling Pathway.

The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer's disease (AD) mouse model. However, there are few reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin 17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD.

A Nucleoside/Nucleobase-Rich Extract from Cordyceps Sinensis Inhibits the Epithelial-Mesenchymal Transition and Protects against Renal Fibrosis in Diabetic Nephropathy.

Cordyceps Sinensis, a traditional Chinese medicine and a healthy food, has been used for the treatment of kidney disease for a long time. The aim of present study was to isolate a nucleoside/nucleobase-rich extract from Cordyceps Sinensis (CS-N), determine the contents of nucleosides and nucleobases, and explore its anti-diabetic nephropathy activity. CS-N was isolated and purified by using microporous resin and glucan columns and the unknown compounds were identified by using HPLC-DAD and LC-MS. The effects of CS-N on the epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) depositions, and the MAPK signaling pathway were evaluated in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-exposed HK-2 cells. CS-N significantly attenuated the abnormity of renal functional parameters, ameliorated histopathological changes, and inhibited EMT and ECM accumulation by regulating p38/ERK signaling pathways. Our findings indicate that CS-N exerts a therapeutic effect on experimental diabetic renal fibrosis by mitigating the EMT and the subsequent ECM deposition with inhibition of p38 and ERK signaling pathways.

DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation.

BACKGROUND: Ubiquitin E3 ligase CUL4A plays important oncogenic roles in the development of cancers. DTL, one of the CUL4-DDB1 associated factors (DCAFs), may involve in the process of cancer development. Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in cell apoptosis, transformation, invasion and tumor progression. METHODS: Affinity-purification mass spectrometry was used to identify potential DTL interaction proteins. Co-immunoprecipitation (Co-IP) was performed to verify protein interaction between DTL and PDCD4. mRNA levels in cancer cells and tissues were detected by Quantitative real-time PCR. Lentivirus was used to establish stable overexpression and knocking down cell lines for DTL and PDCD4. Transwell and wound healing assays were used to determine migration ability of cancer cells. Matrigel assay was used to determine invasion ability of cancer cells. MTT and colony formation assays were used to evaluate proliferation of cancer cells. RESULTS: In this study, programmed cell death 4 (PDCD4) was identified as a potential substrate of DTL. Co-IP and immunofluorescence assays further confirmed the interaction between DTL and PDCD4. Moreover, DTL overexpression decreased the protein level and accelerated the degradation rate of PDCD4. Through in vitro ubiquitination experiment, we proved that PDCD4 was degraded by DTL through ubiquitination. Clinically DTL was significantly up-regulated in cancer tissues than that in normal tissues. The survival curves showed that cancer patients with higher DTL expression owned lower survival rate. Functional experiments showed that DTL not only enhanced the proliferation and migration abilities of cancer cells, but also promoted the tumorigenesis in nude mice. Rescued experiment results demonstrated that silencing PDCD4 simultaneous with DTL recovered the phenotypes defect caused by DTL knocking down. CONCLUSIONS: Our results elucidated that DTL enhanced the motility and proliferation of cancer cells through degrading PDCD4 to promote the development of cancers.

SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination.

BACKGROUND: S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear. METHODS: To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor. RESULTS: We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo. CONCLUSIONS: We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.

Water extract of ginseng and astragalus regulates macrophage polarization and synergistically enhances DDP's anticancer effect.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, supplementing Qi and strengthening body resistance are an important principle of anticancer treatment. Panax ginseng C.A.Mey. (ginseng) and Astragalus membranaceus Bunge (astragalus) are the representative herbs for this therapeutic principle. AIM OF THE STUDY: This study aims to explore the effect of the water extract of ginseng and astragalus (WEGA) on regulating macrophage polarization and mediating anticancer in the tumor microenvironment. MATERIALS AND METHODS: A549 cells were cultured in tumor-associated macrophage (TAM) supernatant with various concentrations of WEGA (0, 5, 10, 20 mg/mL). A549 cell proliferation was determined through methyl thiazole tetrazolium (MTT) assay and real-time cell analysis (RTCA), respectively. In vivo experiments were performed with a Lewis lung cancer (LLC) xenograft mouse model. Forty-eight mice were divided into six groups and treated with saline, WEGA, or cis-diamine dichloro platinum (DDP) with dosage of WEGA (0, 30, 60, 120 mg/kg body weight/day). The different groups were administered with drugs via oral or intraperitoneal injection once a day for 21 consecutive days. Tumor inhibition rate, spleen index, thymus index, cytokine, protein, and mRNA expression levels were detected in mice. RESULTS: In a co-culture system, WEGA remarkably inhibited A549 cell proliferation, promoted the expression of M1 macrophage markers and inhibited M2 TAMs markers. Therefore, WEGA affected the biological behavior of cancer cells by regulating the expression of some markers relevant to macrophage polarization. In addition, the group of WEGA and DDP chemotherapy effectively inhibited the transplanted tumor growth in mice and improved weight loss and immunosuppressive with the cisplatin inducing. CONCLUSIONS: This study provides mechanistic insights into the anticancer effect of WEGA through the regulation of macrophage polarization and highlights that WEGA could be a novel option for integrative cancer therapies.

TCEA1 regulates the proliferative potential of mouse myeloid cells.

Leukemia is a malignance with complex pathogenesis and poor prognosis. Discovery of noval regulators amenable to leukemia could be of value to gain insight into the pathogenesis, diagnosis and prognosis of leukemia. Here, we conducted a large-scale shRNA library screening for functional regulators in the development of myeloid cells in primary cells. We identified eighteen candidate regulators in the primary screening. Those genes cover a wide range of cellular functions, including gene expression regulation, intracellular signaling transduction, nucleotide excision repair, cell cycle control and transcription regulation. In both primary screening and validation, shRNAs targeting Tcea1, encoding the transcription elongation factor A (SII) 1, exhibited the greatest influence on the proliferative potential of cells. Knocking down the expression of Tcea1 in the 32Dcl3 myeloid cell line led to enhanced proliferation of myeloid cells and blockage of myeloid differentiation induced by G-CSF. In addition, silence of Tcea1 inhibited apoptosis of myeloid cells. Thus, Tcea1 was identified as a gene which can influence the proliferative potential, survival and differentiation of myeloid cells. These findings have implications for how transcriptional elongation influences myeloid cell development and leukemic transformation.

miR-1204 targets VDR to promotes epithelial-mesenchymal transition and metastasis in breast cancer.

Plasmacytoma variant translocation 1 (PVT1) is an lncRNA that plays vital roles in breast cancer (BC) pathogenesis. Increasing evidence suggests that miRNAs that reside in the PVT1 locus are the main driver of the oncogenic roles of PVT1 in cancer. However, the oncogenic role and underlying mechanism of miR-1204, located in the PVT1 locus, in human cancer is still unclear. In this study, we discovered that increased expression of miR-1204 is associated with poor prognosis in BC. Moreover, miR-1204 promotes proliferation, epithelial-mesenchymal transition and invasion of BC cells both in vitro and in vivo. Mechanistic investigations demonstrated that VDR is a novel target gene of miR-1204. Interference of VDR restored miR-1204-mediated BC cell proliferation, tumorigenesis, and metastasis. Collectively, our results demonstrated that the miR-1204-VDR pathway exerts oncogenic effects in BC with potential therapeutic applications in blocking BC development and progression.

Suppression of CUL4A attenuates TGF-ß1-induced epithelial-to-mesenchymal transition in breast cancer cells.

Transforming growth factor-ß1 (TGF-ß1) plays a vital role in the process of epithelial-to-mesenchymal transition (EMT) in breast cancer and the cullin 4A (CUL4A) gene is overexpressed in primary breast cancer. However, whether TGF-ß1 signaling can induce CUL4A expression has not been investigated to date, at least to the best of our knowledge. In this study, using breast cancer cell lines, we found that the CUL4A expression level was increased following EMT induced by TGF-ß1. Silencing CUL4A expression or CUL4A inhibition by thalidomide suppressed the EMT process induced by TGF-ß1. We also found that CUL4A was associated with the expression of zinc finger E-box-binding homeobox 1 (ZEB1) which was induced by TGF-ß1. These results suggest that CUL4A is upregulated in TGF-ß1-induced EMT, and has a regulatory function in this process. The identification of CUL4A as a downstream target of TGF-ß1 represents a critical pro-survival mechanism in breast cancer progression and provides another point for therapeutic intervention in breast cancer.

[Corrigendum] Suppression of CUL4A attenuates TGF-ß1-induced epithelial-to-mesenchymal transition in breast cancer cells.

Following the publication of this article, a reader drew to our attention an anomaly associated with the data presented in Fig. 8. The reader found that the two images of the Control group treated with TGF-ß1 in Fig. 8 have some overlap. After careful scrutiny, we found that we somehow misused a migation image for invasion (lower pannel) when constructing the final figure. This does not affect the interpretation of the experiments and the conclusions of the study. A corrected version of Fig. 8 is presented here. We would like to thank the reader of our article for drawing this matter to our attention. [the original article was published in the International Journal of Molecular Medicine 40: 1114-1124, 2017; DOI: 10.3892/ijmm.2017.3118].

A short synthetic peptide fragment of human C2ORF40 has therapeutic potential in breast cancer.

C2ORF40 encodes a secreted protein which is cleaved to generate soluble peptides by proteolytic processing and this process is believed to be necessary for C2ORF40 to exert cell type specific biological activity. Here, we reported a short mimic peptide of human C2ORF40 acts potential therapeutic efficacy in human cancer cells in vitro and in vivo. We synthesized a short peptide of human C2ORF40, named C2ORF40 mimic peptide fragment and assessed its biological function on cancer cell growth, migration and tumorigenesis. Cell growth assay showed that C2ORF40 mimic peptide fragment significantly suppressed cell proliferation of breast and lung cancer cells. Moreover, C2ORF40 mimic peptide fragment significantly inhibited the migration and invasion of breast cancer cells. Furthermore, we showed that this peptide suppressed tumorigenesis in breast tumor xenograft model. Cell cycle assay indicated that the C2ORF40 mimic peptide fragment suppressed the growth of tumor cells through inducing mitotic phase arrest. In conclusion, our results firstly suggested that this short synthetic peptide of human C2ORF40 may be a candidate tumor therapeutic agent.