Asparaginyl endopeptidase (AEP) regulates myocardial apoptosis in response to radiation exposure via alterations in NRF2 activation

xlomafota13 shared this article with you from Inoreader Asparaginyl endopeptidase (AEP) regulates myocardial apoptosis in response to radiation exposure via alterations in NRF2 activation Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1206-1225. eCollection 2021. ABSTRACT Radiation-induced heart disease (RIHD) leads to myocardial dysfunction and metabolic abnormalities in patients treated with thoracic irradiation which restricts the long-term survival benefits of radiotherapy. There is no specific or effective manner of intervention currently available. Asparaginyl endopeptidase (AEP) plays a pivotal role in the maintenance of cellular functions through regulating proteolytic cleavage as peptidase enzyme. We aimed to investigate the role of unique cardiac AEP in cardiac function by modulating key signaling elements in the myocardium. The murine heart was exposed to a single dose of 14 Gy radiation. Cellular signaling and apoptosis was analyzed in human and rat cardiomyocytes treated with various doses of radiation, we observed expression of AEP was increased by immunohistochemical staining in murine heart exposed to radiation. The AEP production along with its increased level of mRNA expression was associated with increased doses of radiation (0, 2, 5, 10 Gy) in cardiomyocytes. The myocardial cells transfected with AEP overexpression showed overall cellular viability enhancement, DNA damage inhibition, the foci formation of γ-H2AX suppressed and DNA repair enhancement significantly after radiation exposure. Small interfering RNA-mediated AEP knockdown was with reduced cardiomyocyte viability, elevated apoptotic rate, increased γ-H2AX foci formation and inhibited DNA repair as well after irradiation. After radiation exposure of 10 Gy, the expression of AEP increased in P53 overexpressing cardiomyocytes and decreased in the P53 knockdown cells, indicates that radiation-induced expression of AEP might be regulated by P53. Moreover, treatments with either AEP overexpression or knockdown showed enhanced NRF2 activity in the nuclear or suppressed NRF2 expression in the cytoplasm of myocardial cells after irradia tion, respectively, defined a possible regulatory effect of AEP associated with diminished NRF2 translocation and activation by radiation exposure, including impair myocardium and myocardial apoptosis. These findings suggest that increased levels of AEP in failing myocardium after irradiation is mediated by P53 and regulate a novel pathway that involves NRF2 activation. AEP is essential for maintaining cellular redox homeostasis of cardiac function. PMID:33948354 | PMC:PMC8085837 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

TM2D1 contributes the epithelial-mesenchymal transition of hepatocellular carcinoma via modulating AKT/β-catenin axis

xlomafota13 shared this article with you from Inoreader TM2D1 contributes the epithelial-mesenchymal transition of hepatocellular carcinoma via modulating AKT/β-catenin axis Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1557-1571. eCollection 2021. ABSTRACT Various epidemiology studies showed the correlation between Alzheimer's disease (AD) and low incidence of cancer. However, the etiology underlying etiology of AD-related carcinogenesis remains largely elusive. Our study focused on characterizing the role of TM2D1 (TM2 domain containing 1) in hepatocellular carcinoma. TM2D1 is also known as β-amyloid peptide binding protein and is critical to the pathogenesis of AD. We found that TM2D1 is increasingly expressed in HCC tumors relative to the peritumoral tissues of the matched tumors and high TM2D1 expression predicts unfavorable clinical outcomes. TM2D1 overexpression induced HCC cell proliferation, migration and invasion, which was related to the epithelial-mesenchymal transition (EMT) observed in these cells. Conversely, TM2D1 depletion led to opposite phenotype in HCC. Mechanistically, we found that TM2D1 promot ed Akt and β-catenin hyper-activation, which corresponded with molecular marker change in EMT signaling pathway. Taken together, our results indicated that TM2D1 played an important role in the EMT process in HCC cells by activating AKT and β-catenin signaling and may become a promising therapeutic target in HCC. PMID:33948373 | PMC:PMC8085884 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cordycepin inhibits the proliferation of malignant peripheral nerve sheath tumor cells through the p53/Sp1/tubulin pathway

xlomafota13 shared this article with you from Inoreader Cordycepin inhibits the proliferation of malignant peripheral nerve sheath tumor cells through the p53/Sp1/tubulin pathway Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1247-1266. eCollection 2021. ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. In addition to skin pigmentation and cutaneous neurofibroma, some patients developed the plexiform neurofibroma since birth. Plexiform neurofibroma has abundant Schwann cells, fibroblasts, mast cells, blood vessels, and connective tissues, which increases the risk of developing a malignant peripheral nerve sheath tumor (MPNST). MPNST is a highly invasive cancer with no effective therapeutic agent. Cordycepin or 3'-deoxyadenosine is an extract from cordyceps militaris, which has been reported as an anti-inflammation and anti-tumor agent. Herein, we evaluated cordycepin's anti-proliferative effect on MPNST cell lines both in vitro and in vivo. Cordycepin inhibited the MPNST cell growth with an arrest of cell cycle at G2/M and S phases. The administration of na ringin and pentostatin, inhibitors for adenosine deaminase (ADA), enzyme responsible for cordycepin degradation, did not show a synergistic effect in MPNST cells treated with cordycepin. However, the combined treatment enhanced the decrease of tumors in xenograft mouse model. Immunoblotting showed a decreased level of p53 protein in all MPNST cell lines, but S462TY cells. After cordycepin treatment, the levels of ERK, survivin, pAKT, and Sp1 proteins also decreased. The level of tubulin, but not actin or GAPDH, decreased in a dose-dependent manner. The microtubule network which is composed of tubulins was markedly decomposed in those treated MPNST cells. To elucidate the epigenetic control of transcription, ChIP-qPCR assay of the Sp1 and tubulin promoter regions revealed decreased Sp1 binding. The incorporation of 3'-doexyadenosine is detrimental for the process of poly(A) tail elongation. The poly(A) tail length assay showed the tail length in Sp1 and tubulin transcripts decreased in the treated cells. Nevertheless, the administration of SP1 protein to the treated cells could not rescue them completely. Furthermore, the p53-knocked-down cells (S462TY) where the expression of both p53 and Sp1 was suppressed, were vulnerable to cordycepin. The p53 protein could ameliorate the effect. In summary, cordycepin is effective to inhibit the growth of MPNST, probably through the pathway of p53/Sp1/tubulin. PMID:33948356 | PMC:PMC80858 85 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Elevated LOXL2 expression by LINC01347/miR-328-5p axis contributes to 5-FU chemotherapy resistance of colorectal cancer

xlomafota13 shared this article with you from Inoreader Elevated LOXL2 expression by LINC01347/miR-328-5p axis contributes to 5-FU chemotherapy resistance of colorectal cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1572-1585. eCollection 2021. ABSTRACT Chemotherapy resistance after curative surgery is a major contributor to the mortality of colorectal cancer (CRC). Detailed mechanism studies of specific molecular alterations are critical to improving the available therapies for long-term disease administration. We explored the functional role of LINC01347 in chemotherapy resistance of CRC. Elevated LINC01347 expression was correlated with CRC disease progression during chemotherapy treatment. However, the functional role of LINC01347 and mechanism remained undefined. In this study, we demonstrated that elevated LINC01347 expression was correlated with late clinical stage and poor prognosis in CRC tumor tissues with TCGA data. Exogenous LINC01347 expression promoted cell proliferation and 5-FU resistance of CRC cells, while LINC01347 knockdown attenuated cell growth and 5-FU resistance in vitro and in vivo. Molec ular analysis indicated that LINC01347 participated in the transcriptional regulation of LOXL2 by sponging miR-328-5p. LOXL2 knockdown impaired the LINC01347 overexpression induced 5-FU resistance in CRC cells. The clinical analysis supported miR-328-5p/LOXL2 as a candidate biomarker for chemotherapy resistance of CRC patients. Our study provided a molecular basis for the development of 5-FU based chemotherapy resistance in CRC by LINC01347/miR-328/LOXL2 axis. We identified LINC01347 as a prognostic biomarker and potential therapeutic target against 5-FU based chemotherapy resistance of CRC. PMID:33948374 | PMC:PMC8085882 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pinin promotes tumor progression via activating CREB through PI3K/AKT and ERK/MAPK pathway in prostate cancer

xlomafota13 shared this article with you from Inoreader Pinin promotes tumor progression via activating CREB through PI3K/AKT and ERK/MAPK pathway in prostate cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1286-1303. eCollection 2021. ABSTRACT Pinin (PNN), a desmosome associated protein, was demonstrated to be over-expressed and act as a tumor-promoting factor in ovarian cancer, hepatocellular carcinoma and colorectal cancer. However, the precise role of PNN in prostate cancer is still unknown. In the study, we reported that PNN was upregulated in prostate cancer tissues and PNN expression was positively associated with Gleason score, tumor stage and tumor metastasis. PNN promoted cell growth and tumorigenicity in vitro and in vivo, and modulated cell growth through driving G1/S transition via CDK6, CDK2, and Cyclin D1 in prostate cancer cells. Furthermore, PNN accelerated cell invasion, migration and EMT processes of prostate cancer cells, accompanied with the up-regulation of MMP-2, MMP-9, N-cadherin, Vimentin and down-regulation of E-cadherin. Mechanism study demonstrated that the proli feration- and motility-promoting effects of PNN on prostate cancer cells dependent on the activation of CREB, which was reversed by CREB inhibition. More important, PNN activated CREB via PI3K/AKT and ERK/MAPK pathway. Collectively, these findings indicated that PNN plays important roles in prostate cancer tumorigenesis and progression and it is a potential therapeutic target for prostate cancer treatment. PMID:33948358 | PMC:PMC8085840 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

ImmunoPET of the differential expression of CD146 in breast cancer

xlomafota13 shared this article with you from Inoreader ImmunoPET of the differential expression of CD146 in breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1586-1599. eCollection 2021. ABSTRACT With advancement in antibody engineering, the development and characterization of new cancer-specific molecular targets are in the forefront of this PET-antibody combination "revolution". Overexpression of CD146 in different types of tumors, including breast tumor, has been associated with tumor progression and poor prognosis. Non-invasive detection of CD146 with a monoclonal antibody may provide a noninvasive diagnostic tool with high specificity and accountability. METHODS: Herein, we have developed a CD146-specific monoclonal antibody (YY146), radiolabeled it with 52Mn and 89Zr and identified its capability in acting as a non-invasive imaging agent that specific targets CD146 in different murine breast cancer models. CD146 expression was first screened in different breast tumor cell lines through Western Blot and confirmed its bindin g ability to YY146 using Flow Cytometry. Serial immunoPET images were carried out after intravenous administration of 52Mn or 89Zr labeled YY146. In addition, we also performed in vivo fluorescence imaging in animals injected with YY146 conjugated with Cy5.5. RESULTS: Western Blot results show that MDA-MB-435 cell line had greater levels of CD146 expression when compared to the other cell lines investigated. Flow cytometry confirmed binding ability of YY146. PET images revealed well correlated uptake between tumor uptake and CD146 expression levels, confirmed by biodistribution studies and fluorescence imaging. CONCLUSION: PET imaging, for up to 7 days, of mice bearing three different breast tumors were carried out and revealed radiotracer uptake in tumors that strongly (r2 = 0.98, P < 0.01), correlated with CD146 expression levels, as confirmed by in vitro and ex vivo studies. PMID:33948375 | PMC:PMC8085863 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

125I seed implantation brachytherapy for glottic carcinoma: an experimental and clinical study

xlomafota13 shared this article with you from Inoreader <sup>125</sup>I seed implantation brachytherapy for glottic carcinoma: an experimental and clinical study Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1321-1334. eCollection 2021. ABSTRACT 125I seed implantation brachytherapy (ISIB) is the preferred treatment for prostate cancer. Is ISIB technically suitable for glottic carcinoma (GC)? This question has not been answered in the literature; thus, the present study was carried out to evaluate the feasibility and effect of ISIB on GC in animal and clinical studies. An animal model of Tu-212 cell laryngeal carcinoma xenografts (n = 20 animals) underwent ISIB treatments [experimental group (EG) using 0.8-mCi/seed, control group (CG) using 0-mCi/seed]; at 4 weeks, haematoxylin-eosin (HE) staining was performed, and the mRNA and protein expression of Bax, Bcl-2 and PCNA was analysed. Moreover, thirty healthy beagle dogs underwent ISIB under CT guidance (EG, 0.8 mCi/seed, CG, 0 mCi/seed), and injuries to the normal tissue were analysed by HE and Masson staining at 2, 4, and 8 weeks. Finally, twen ty-one GC patients (T2-3N0M0) underwent percutaneous ISIB at a mean prescription dose of 116.8 Gy; the technical success, complications, local tumour response, voice quality, local progression and overall survival were analysed. The results showed that the xenograft tumours were significantly inhibited in the EG. The Bax protein levels were significantly increased in this group (P<0.05), while the Bcl-2 and PCNA protein levels were decreased (P<0.05). Moreover, the glottic injury scores increased with the dose accumulation (P<0.05), while the adjacent tissue did not show pathohistological injury, and the routine blood tests showed no change between the pre-treatment baseline levels and the levels 2, 4, or 8 weeks later (P>0.05). The clinical study found that the rate of technical success was 100% with no procedure-related complications; furthermore, complete response was achieved in all patients, and no local progression occurred. All patients survived and showed improve ments in their voice quality (P<0.05) during the follow-up period (median 23.5 months). The results show that ISIB is a safe and effective treatment for GC; randomized controlled trials are needed to further evaluate its clinical efficacy. PMID:33948360 | PMC:PMC8085880 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

New insight into the role of ANXA1 in melanoma progression: involvement of stromal expression in dissemination

xlomafota13 shared this article with you from Inoreader New insight into the role of ANXA1 in melanoma progression: involvement of stromal expression in dissemination Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1600-1615. eCollection 2021. ABSTRACT ANXA1, first described in the context of inflammation, appears to be deregulated in many cancers and increased in melanomas compared with melanocytes. To date, few studies have investigated the role of ANXA1 in melanoma progression. Furthermore, this protein is expressed by various cell types, including immune and endothelial cells. We therefore analyzed the specific roles of ANXA1 using melanoma and stromal cells in two human cell lines (A375-MA2 and SK-MEL-28) in vitro and in Anxa1 null C57Bl6/J mice bearing B16Bl6 tumors. We report decreased proliferation in both ANXA1 siRNA A375-MA2 and SK-MEL-28, but cell-dependent effects of ANXA1 in migration in vitro. However, we also observed a significant decrease of B16Bl6 tumor growth associated with a reduction of Ki-67 positive cells in Anxa1 null mice compared with wild-type mice. Interes tingly, we also found a significant reduction of spontaneous metastases, which can be attributed to decreased angiogenesis concomitantly with greater immune cell presence in the Anxa1 null stromal context. This study highlights the pejorative role of ANXA1 in both tumor and stromal cells in melanoma, due to its involvement in proliferation and angiogenesis. PMID:33948376 | PMC:PMC8085877 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

BLM interaction with EZH2 regulates MDM2 expression and is a poor prognostic biomarker for prostate cancer

xlomafota13 shared this article with you from Inoreader BLM interaction with EZH2 regulates MDM2 expression and is a poor prognostic biomarker for prostate cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1347-1368. eCollection 2021. ABSTRACT Prostate cancer (PCa) is one of the major causes of cancer death among males worldwide. Our previous studies indicated that the proliferation of prostate cancer cells was reduced after BLM knockdown, however, the mechanism is still not clear. In this study, we identified a direct interaction between BLM and EZH2, which had extremely significantly positive correlations (P<0.001). In vitro, our research revealed that tumor growth was inhibited after EZH2 knockdown and that inhibition could be reversed by BLM overexpression; conversely, tumor growth was promoted after EZH2 overexpression, and promotion could be reversed by BLM knockdown. This suggests that BLM and EZH2 play important roles in the progression of prostate cancer cells. In vivo, the impact of BLM and EZH2 was investigated in mouse xenograft models, and the results showed that EZH 2 could be regulated by BLM, which was consistent with our in vitro observations. Our results demonstrated that the expression of P53 is affected by the binding of BLM and EZH2 to the MDM2 promoter region. This finding indicated that EZH2 regulates the expression of MDM2 at the transcriptional level by interacting with BLM. PMID:33948362 | PMC:PMC8085859 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Concurrence of Myelodysplastic syndromes and large granular lymphocyte leukemia: clinicopathological features, mutational profile and gene ontology analysis in a single center

xlomafota13 shared this article with you from Inoreader Concurrence of Myelodysplastic syndromes and large granular lymphocyte leukemia: clinicopathological features, mutational profile and gene ontology analysis in a single center Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1616-1631. eCollection 2021. ABSTRACT The concurrence of Myelodysplastic syndromes (MDS) and large granular lymphocyte leukemia (LGLL) has been reported in a small group of patients and might suggest an etiologic relationship rather than a simple coincidence. In this present study, clinicopathological features were detailed in ten cases of MDS concurrent with LGLL (MDS-LGLL). These cases included seven patients with T-LGLL, two with mixed-phenotype LGLL, and one with CLPD-NK. Subsequently, gene mutation screening for commonly myeloid-related or lymphoid-related genes was performed in MDS-LGLL patients by using next generation sequencing (NGS). The genes with the highest frequency of mutations were ASXL1 (3/10, 30%) and STAG2 (3/10, 30%) among a panel of 114 genes. LGLL-associated mutations of STAT3 (2/10, 20%) and STAT5b (1/10, 10%) were also detected. Moreover, whole-exome sequencing (WES) and gene ontology (GO) analysis for one patient in his different phases revealed increased enrichment of histone H3 lysine 4 (H3K4) mono-methylation (GO:0097692) pathway and decreased enrichment of translocation of ZAP-70 to immunological synapse (R-HAS-202430) pathway upon progression from MDS to MDS-LGLL. PMID:33948377 | PMC:PMC8085857 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Lycorine hydrochloride inhibits melanoma cell proliferation, migration and invasion via down-regulating p21Cip1/WAF1

xlomafota13 shared this article with you from Inoreader Lycorine hydrochloride inhibits melanoma cell proliferation, migration and invasion via down-regulating p21<sup>Cip1/WAF1</sup> Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1391-1409. eCollection 2021. ABSTRACT Lycorine hydrochloride (LH) is an active ingredient sourced from the medicinal herb Lycoris radiata. Previous studies have suggested that LH exerts tumor suppression activity in several human cancers. However, the anti-cancer effect of LH in melanoma and the potential molecular mechanisms still need to be further studied. p21Cip1/WAF1, unlike its traditional cyclin-dependent kinase (CDK) inhibitor role, is believed to act as an oncogene under certain cellular conditions. In this research, an increased expression of p21Cip1/WAF1 was found in human melanoma tissues and positively related to the tumor invasion depth. High level of p21Cip1/WAF1 was found to correlate with bad outcomes of melanoma patients by Kaplan-Meier survival analysis. Functional experiments demonstrated that the proliferation, migration and invasion ability of A375 and MV3 melanoma cells was powerfully inhibited by LH through inducing S phase cell cycle arrest and regulating epithelial-mesenchymal transition (EMT). In NOD/SCID mice model, LH effectively inhibited the xenograft tumor growth and lung metastasis of A375 cells. Further research revealed that LH reduced p21Cip1/WAF1 protein by accelerating its ubiquitination. Importantly, the LH-induced suppression of cell proliferation and metastasis was rescued by p21Cip1/WAF1 overexpression, both in vitro an in vivo. Taken together, LH, which suppresses the proliferation and metastasis of melanoma cells via down-regulating p21Cip1/WAF1, is expected to be developed as an effective medicine for melanoma therapy. PMID:33948364 | PMC:PMC8085853 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.