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Open accessJournal ArticleDOI: 10.1038/S41698-021-00152-9

Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance

02 Mar 2021-Vol. 5, Iss: 1, pp 16
Abstract: Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients' serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.

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Topics: Ovarian tumor (64%), Ovarian cancer (60%), Ovarian carcinoma (57.99%) ... show more

5 results found

Open accessJournal ArticleDOI: 10.1186/S12935-021-02078-5
Huilin Zhang1, Ping He2, Qing Zhou1, Yan Lu1  +1 moreInstitutions (2)
Abstract: CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

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Topics: HeLa (56.99%), Cell cycle (54%), Protein neddylation (54%) ... show more

Journal ArticleDOI: 10.1158/0008-5472.CAN-21-0483
Anjali Geethadevi1, Ajay Nair2, Deepak Parashar1, Zhiqiang Ku3  +17 moreInstitutions (4)
15 Oct 2021-Cancer Research
Abstract: Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling in vitro. Importantly, these antibody clones inhibited the growth of ovarian cancer cells in vitro and in vivo by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.

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Topics: Oncostatin M receptor (61%), Oncostatin M (61%), Ovarian cancer (54%) ... show more

Open accessJournal ArticleDOI: 10.2147/OTT.S295125
Yongguo Liu1, Jing Liu, Xiancheng Han1, Linkai Mou1Institutions (1)
Abstract: Purpose miRNAs can act as oncogenes or tumor suppressors and participate in the development and progression of tumors, thus affecting the prognosis and survival of cancer patients. In this paper, we mainly studied the role of miR-1826 in prostate cancer. Patients and methods The expression of miR-1826 was studied by quantitative real-time PCR (qRT-PCR). Kaplan-Meier curves were used to analyze the relationship between the expression of miR-1826 and the survival rate of PC patients. Cox regression analysis was used to study the risk factors affecting the prognosis of PC patients. PC cells were transfected with miR-1826 mimic, mimic negative control (mimic NC), miR-1826 inhibitor, or inhibitor NC. The effect of miR-1826 on the proliferation of PC cells was studied by the CCK-8 method and colony formation assay. Transwell assays were used to detect the effect of miR-1826 on the migratory and invasive abilities of tumor cells. Results The expression of miR-1826 in PC tissues was lower than that in adjacent normal tissues, and that the expression levels of miR-1826 in four PC cell lines were all lower than normal human prostate epithelial cell lines. Patients with low expression of miR-1826 had shorter overall survival compared with those with high expression. The downregulation of miR-1826 promoted PC cell proliferation, migration, and invasion. Conclusion In summary, the low expression of miR-1826 may promote the progression of PC, and the low expression of miR-1826 is also associated with a poor prognosis in PC patients.

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Topics: Tumor progression (59%), Prostate cancer (53%), Cancer (53%) ... show more

Journal ArticleDOI: 10.1016/J.MAM.2021.101039
Abstract: The influence of environmental factors on an individual, from conception onwards, is defined as the exposome. It can be categorized into the external exposome, which includes external factors such as air pollution, chemical contaminants, and diet, and the internal exposome, which is unique to an individual, and involves age, physiology, and their genetic profile. The effect of external exposures on the internal exposome, or genetic profile, can be determined through omics analyses. However, this is often compromised due to low sample quantity and cost. Therefore, identification of other factors that can provide an insight into the cellular profile of an individual, provides an exciting avenue, and an emerging field is that of extracellular vesicles (EVs). Recently, our understanding of how cells can communicate with each other has shifted to recognise the role of EVs. EVs are secreted by all living cells, and have been identified in all biological fluids studied so far. They transport bioactive molecules (e.g., proteins, miRNAs, and DNA), and their release can be regulated by the cellular microenvironment. Analysis of EVs in respond to environmental factors might provide novel insights into the role of tumour EVs in carcinogenesis. Not only will EVs give some insight into the tumour cells themselves but they will also provide a better understanding of how cells communicate with one another, contributing to cancer progression. Moreover, characterising the content and functions of tumour-derived EVs has the potential to overcome the current challenges to improve cancer patient outcomes. For example, the identification of EVs targets for therapeutic interventions and tumour EVs biomarkers could facilitate the development of early screening for several cancers. The aim of this review, thus, is to discuss the overall role of EVs in response to the various external and internal signals in cancer. We will specifically highlight the biogenesis, secretion, and content of EVs in response to oncogenic transformation and metabolic regulators in cancer.

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Topics: Exposome (60%), Extracellular vesicle (52%)

Open accessJournal ArticleDOI: 10.1080/21655979.2021.1989259
12 Oct 2021-Bioengineered bugs
Abstract: The competing endogenous RNA (ceRNA) activity of circular RNAs (circRNAs) has been implicated in the development of gastric cancer. Here, we sought to explore the ceRNA function of circRNA Jupiter microtubule associated homolog 1 (circ_HN1) in gastric tumorigenesis. Circ_HN1, microRNA (miR)-628-5p, and NT5E expression levels were quantified by qRT-PCR and western blot. Dual-luciferase reporter assays were used to assess the direct relationship between miR-628-5p and circ_HN1 or NT5E. Our data showed that circ_HN1 expression was enhanced in human gastric cancer. Depletion of circ_HN1 impeded cell proliferation, spheroid formation, invasion, and migration and promoted apoptosis in vitro, as well as diminished tumor growth in vivo. NT5E was a downstream effector of circ_HN1 function. NT5E was targeted and inhibited by miR-628-5p through the perfect complementary site in NT5E 3'UTR, and circ_HN1 affected NT5E expression through miR-628-5p competition. Moreover, depletion of miR-628-5p reversed the effects of circ_HN1 silencing on regulating cell functional behaviors. Our findings identify a novel ceRNA network, the circ_HN1/miR-628-5p/NT5E axis, for the oncogenic activity of circ_HN1 in gastric cancer, highlighting circ_HN1 inhibition as a promising targeted treatment against gastric cancer.

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Topics: Competing endogenous RNA (52%), microRNA (51%)


40 results found

Open accessJournal ArticleDOI: 10.1038/S41598-018-27521-Y
15 Jun 2018-Scientific Reports
Abstract: Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.

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771 Citations

Open accessJournal ArticleDOI: 10.1038/S41598-018-19339-5
16 Jan 2018-Scientific Reports
Abstract: Breast cancer remains the most prevalent cause of cancer mortality in woman worldwide due to the metastatic process and therapy resistance. Resistance against cancer therapy is partially attributed to cancer stem cells (CSCs). These cells arise from epithelial cells undergoing epithelial-to-mesenchymal transition (EMT) and might be responsible for tumor recurrence. In this study, we reported the relevance of miR-155 upregulation in chemoresistant cells associated with EMT. Notably, we found miR-155 induction in exosomes isolated from CSCs and resistant cells, followed by resistant cells' exosome transfer to the recipient sensitive cells. Functionally, miR-155 mimic assay showed an enrichment in miR-155 from exosome concomitant with miR-155 exosome transfer to breast cancer cells. In parallel to these effects, we also observed EMT change in miR-155 transfected cells. The chemoresistance phenotype transfer to sensitive cells and the migration capability was analyzed by MTT and scratch assays and our results suggest that exosomes may intermediate resistance and migration capacity to sensitive cells partly through exosome transfer of miR-155. Taken together, our findings establish the significance of exosome-mediate miR-155 chemoresistance in breast cancer cells, with implications for targeting miR-155 signaling as a possible therapeutic strategy.

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Topics: Cancer stem cell (64%), Exosome (60%), Transfection (52%) ... show more

145 Citations

Open accessJournal ArticleDOI: 10.1038/BJC.2017.18
Abstract: Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK

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137 Citations

Journal ArticleDOI: 10.1006/BBRC.2001.4250
Kazue Yamamoto, Aikou Okamoto1, Seiji Isonishi1, Kazunori Ochiai1  +1 moreInstitutions (1)
Abstract: In the screening for cisplatin (CDDP)-resistance related genes by a mRNA differential display method, we detected some increased bands in CDDP resistant ovarian tumor cell line 2008/C13*5.25. One of them, named DD9, was a positive fragment on Northern blot analysis. We cloned it as a full length cDNA by 5'RACE and found a novel gene, CRR9 (Cisplatin Resistance Related gene 9). The CRR9 gene was transcribed into a 2.0 kb mRNA, encoding 512 amino acids. The putative protein had transmembrane-like domains and well conserved on C terminus with human CLPTM1 and the homologs found in Drosophila and C. elegans. Transfection assay showed that the CDDP-sensitive strain 2008 with CRR9 was more sensitive to CDDP, indicating that CRR9 was not associated with the CDDP-resistance, but the CDDP-induced apoptosis.

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Topics: Differential display (55%), Northern blot (54%), Gene expression profiling (52%) ... show more

132 Citations

Open accessJournal ArticleDOI: 10.1073/PNAS.0907939106
Abstract: Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.

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101 Citations

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