Cellular OncologyPub Date : 2020-08-06DOI: 10.21203/rs.3.rs-53956/v1
S. Kuo, M. Wei, Yi-Hsuan Lee, Jui-Chueh Lin, Wen-Chi Yang, Shi‐Yi Yang, Chiun-Sheng Huang
{"title":"MAP3K1 expression is associated with progression and poor prognosis of hormone receptor-positive, HER2-negative early-stage breast cancer","authors":"S. Kuo, M. Wei, Yi-Hsuan Lee, Jui-Chueh Lin, Wen-Chi Yang, Shi‐Yi Yang, Chiun-Sheng Huang","doi":"10.21203/rs.3.rs-53956/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-53956/v1","url":null,"abstract":"Purpose In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative early stage breast cancer. Methods Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 [#3] and shMAP3K1 [#5]). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0–3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort. Results In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%, p = 0.003) and overall survival (OS) (81.9% vs. 96.3%, p = 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK ( p < 0.001) and phospho-JNK ( p < 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS. Conclusion Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"1 1","pages":"1-22"},"PeriodicalIF":6.6,"publicationDate":"2020-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45156513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-12-01Epub Date: 2019-09-06DOI: 10.1007/s13402-019-00471-x
Peichen Zhang, Lingyan Shi, Tingting Zhang, Lin Hong, Wei He, Peihai Cao, Xin Shen, Peisen Zheng, Yiqun Xia, Peng Zou
{"title":"Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells.","authors":"Peichen Zhang, Lingyan Shi, Tingting Zhang, Lin Hong, Wei He, Peihai Cao, Xin Shen, Peisen Zheng, Yiqun Xia, Peng Zou","doi":"10.1007/s13402-019-00471-x","DOIUrl":"10.1007/s13402-019-00471-x","url":null,"abstract":"<p><strong>Purpose: </strong>Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells.</p><p><strong>Methods: </strong>Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo.</p><p><strong>Results: </strong>We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment.</p><p><strong>Conclusions: </strong>Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"847-860"},"PeriodicalIF":6.6,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00471-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46083132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-12-01Epub Date: 2019-07-22DOI: 10.1007/s13402-019-00461-z
Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li
{"title":"Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN.","authors":"Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li","doi":"10.1007/s13402-019-00461-z","DOIUrl":"https://doi.org/10.1007/s13402-019-00461-z","url":null,"abstract":"<p><strong>Purpose: </strong>Exosomes play important roles in intercellular communication through signaling pathways affecting tumor microenvironment modulation and tumor proliferation, including those in glioblastoma (GBM). As yet, however, limited studies have been conducted on the inhibitory effect of human bone marrow-derived mesenchymal stem cell (hBMSC)-derived exosomes on GBM development. Therefore, we set out to assess the role of hBMSC secreted exosomes, in particular those carrying microRNA-34a (miR-34a), in the development of GBM.</p><p><strong>Methods: </strong>Microarray-based expression analysis was employed to identify differentially expressed genes and to predict miRNAs regulating MYCN expression. Next, hBMSCs were transfected with a miR-34a mimic or inhibitor after which exosomes were isolated. Proliferation, apoptosis, migration, invasion and temozolomide (TMZ) chemosensitivity of exosome-exposed GBM cells (T-98G, LN229 and A-172) were measured in vitro. The mechanism underlying MYCN regulation was investigated using lentiviral transfections. The in vivo inhibitory effect of exosomal miR-34a was measured in nude mice xenografted with GBM cells through subcutaneous injection of hBMSCs with an upregulated miR34a content.</p><p><strong>Results: </strong>We found that poorly-expressed miR-34a specifically targeted and negatively regulated the expression of MYCN in GBM cells. In addition we found that miR-34a was delivered to T-98G, LN229 and A-172 GBM cells via hBMSC-derived exosomes. Exogenous overexpression of miR-34a in hBMSC-derived exosomes resulted in inhibition of GBM cell proliferation, invasion, migration and tumorigenesis in vitro and in vivo, while promoting the chemosensitivity of GBM cells to TMZ by silencing MYCN.</p><p><strong>Conclusions: </strong>From our data we conclude that hBMSC-derived exosomes overexpressing miR-34a may be instrumental for the therapeutic targeting and clinical management of GBM.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 6","pages":"783-799"},"PeriodicalIF":6.6,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00461-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-11-12DOI: 10.1007/s13402-019-00476-6
Zhiyong Yang, Ning Zhao, J. Cui, Heshui Wu, J. Xiong, T. Peng
{"title":"Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210","authors":"Zhiyong Yang, Ning Zhao, J. Cui, Heshui Wu, J. Xiong, T. Peng","doi":"10.1007/s13402-019-00476-6","DOIUrl":"https://doi.org/10.1007/s13402-019-00476-6","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"11 1","pages":"123 - 136"},"PeriodicalIF":6.6,"publicationDate":"2019-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00476-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52880080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-09-13DOI: 10.1007/s13402-019-00435-1
Chao Song, Tianwei Chen, Lan He, Ning Ma, Jian-ang Li, Y. Rong, Yuan Fang, Mengmeng Liu, D. Xie, W. Lou
{"title":"PRMT1 promotes pancreatic cancer growth and predicts poor prognosis","authors":"Chao Song, Tianwei Chen, Lan He, Ning Ma, Jian-ang Li, Y. Rong, Yuan Fang, Mengmeng Liu, D. Xie, W. Lou","doi":"10.1007/s13402-019-00435-1","DOIUrl":"https://doi.org/10.1007/s13402-019-00435-1","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"43 1","pages":"51 - 62"},"PeriodicalIF":6.6,"publicationDate":"2019-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00435-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52880035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-09-07DOI: 10.1007/s13402-019-00472-w
N. Mizoshiri, T. Shirai, R. Terauchi, S. Tsuchida, Y. Mori, Daichi Hayashi, T. Kishida, Y. Arai, O. Mazda, T. Nakanishi, T. Kubo
{"title":"The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma","authors":"N. Mizoshiri, T. Shirai, R. Terauchi, S. Tsuchida, Y. Mori, Daichi Hayashi, T. Kishida, Y. Arai, O. Mazda, T. Nakanishi, T. Kubo","doi":"10.1007/s13402-019-00472-w","DOIUrl":"https://doi.org/10.1007/s13402-019-00472-w","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"861 - 871"},"PeriodicalIF":6.6,"publicationDate":"2019-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00472-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43622790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular OncologyPub Date : 2019-08-08DOI: 10.1007/s13402-019-00465-9
Á. Quintanal-Villalonga, S. Molina-Pinelo
{"title":"Epigenetics of lung cancer: a translational perspective","authors":"Á. Quintanal-Villalonga, S. Molina-Pinelo","doi":"10.1007/s13402-019-00465-9","DOIUrl":"https://doi.org/10.1007/s13402-019-00465-9","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"42 1","pages":"739 - 756"},"PeriodicalIF":6.6,"publicationDate":"2019-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s13402-019-00465-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45665050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}