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1
Comparative Study Elife
2020 Jul 28;9:e56177. doi: 10.7554/eLife.56177.
Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging
Sebastian I Arriola Apelo 1 2 3, Amy Lin 1 2 3, Jacqueline A Brinkman 2 3, Emma Meyer 1 2 3, Mark Morrison 2 3, Jay L Tomasiewicz 2, Cassidy P Pumper 2 3, Emma L Baar 2 3, Nicole E Richardson 2 3 4, Mohammed Alotaibi 2 3 4, Dudley W Lamming 2 3 4 5
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PMID: 32720643 PMCID: PMC7386906 DOI: 10.7554/eLife.56177
Free PMC article
Abstract
Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.
Keywords: aging; genetics; genomics; healthspan; human biology; mTOR; mTORC2; medicine; mouse; ovariectomy; sex.
Conflict of interest statement
SA, AL, JB, EM, MM, JT, CP, EB, NR, MA No competing interests declared, DL DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.
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2
Retraction of Publication Am J Cancer Res
2021 Feb 1;11(2):623. eCollection 2021.
Long non-coding RNA AK093407 promotes proliferation and inhibits apoptosis of human osteosarcoma cells via STAT3 activation [Retraction]
No authors listed
PMID: 33575092 PMCID: PMC7868756
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Abstract
[This retracts the article on p. 892 in vol. 7, PMID: 28469961.].
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Retraction of
Long non-coding RNA AK093407 promotes proliferation and inhibits apoptosis of human osteosarcoma cells via STAT3 activation.
Wang Y, Liang T, Wang Y, Huang Y, Li Y.
Am J Cancer Res. 2017 Apr 1;7(4):892-902. eCollection 2017.
PMID: 28469961 Free PMC article. Retracted.
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3
Review Am J Cancer Res
2021 Jan 1;11(1):1-13. eCollection 2021.
Progress and assessment of lncRNA DGCR5 in malignant phenotype and immune infiltration of human cancers
Chen Xue 1, Can Chen 1, Xinyu Gu 1, Lanjuan Li 1
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PMID: 33520356 PMCID: PMC7840720
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Abstract
As a special type of noncoding RNA, long noncoding RNAs (lncRNAs) have vital roles during the development of human cancers and may be novel predictors or therapeutic targets for improving the management of patients with cancer. DiGeorge syndrome critical region gene 5 (DGCR5) is a prominent tumor-associated lncRNA, exerting tumor suppressor or oncogenic roles in various cancers. Previous studies have reported that DGCR5 has low expression in most types of cancers but high expression in triple-negative breast cancer, gallbladder cancer, and lung cancer. And DGCR5 expression is related to many hallmarks of cancer types, including cell proliferation, invasion, migration, apoptosis, stemness, and therapeutic responsiveness. Additionally, the pivotal molecules involved in DGCR5 regulation of signaling pathways are attributed to cancer hallmarks related to the pathogenesis of different types of malignant tumors. Herein, we discuss the DGCR5 expression pattern in various types of tumor tiss ues and relationships between DGCR5 expression and immune cell infiltration and immune purity. We also review our current understanding of DGCR5 in carcinogenesis and its potential application as a prognostic biomarker or therapeutic target in human cancers.
Keywords: DGCR5; TCGA; function; human cancers; long noncoding RNA; molecular mechanisms.
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4
Review Am J Cancer Res
2021 Jan 1;11(1):31-42. eCollection 2021.
Application and research progress of organoids in cholangiocarcinoma and gallbladder carcinoma
Yun-Peng Huang 1, Kai Liu 1, Yong-Xiang Wang 1, Yang Yang 1, Li Xiong 1, Zi-Jian Zhang 1, Yu Wen 1
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PMID: 33520358 PMCID: PMC7840717
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Abstract
Both cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC) are belong to biliary tract carcinomas (BTCs) with a high degree of malignancy and a poor prognosis. Therefore, an in vitro model is urgently needed to increase our understanding of the pathogenesis of BTCs. Tumor organoids are a novel three-dimensional (3D) culture technology that utilizes samples from removed tumors. Therefore, it can maintain the histological features, expression profiles and marker expression of the parental tissues. Recently, with the widespread use of this technique, increasing research is beginning to use organoid to study the cellular metabolism, pathogenesis, chemotherapy resistance, and new therapy methods of BTCs. In this review, we will discuss the advantages and disadvantages of BTC organoids compared with other cell culture techniques. In addition, the construction methods, research directions and current limitations of BTC organoids will be described.
Keywords: Cholangiocarcinoma; biliary tract carcinomas; gallbladder carcinoma; organoids.
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5
Am J Cancer Res
2021 Feb 1;11(2):441-457. eCollection 2021.
Isolation and characterization of cancer stem cells derived from human glioblastoma
Hiroko Ishii 1, Yuki Mimura 2, Maram H Zahra 2, Shota Katayama 2, Ghmkin Hassan 2, Said M Afify 2 3, Masaharu Seno 2
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PMID: 33575080 PMCID: PMC7868757
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Abstract
Cancer stem cell (CSC) is considered as a cause of cancer recurrence and metastasis. Simultaneously CSCs are responsible for the heterogeneous population in tumor tissues due to their differentiation potential. However, the characterizations of CSCs are still not enough and cancer stem cell lines widely available is desired to be established for the advancement of cancer research. In this study, we tried to isolate and characterize stem like cells from human glioblastoma cell line U-251MG cells. U-251MG P1 cells, which was previously condensed in the presence of hyaluronic acid as CD44 positive population were subjected to single cell isolation procedure. Although 5 clones were isolated, only one clone exhibited high expression of CD44, Nanog, OCT3/4 and SOX2, and named U-251MGSC1. The sphere forming ability of U-251MGSC1 cell was significantly higher than the parental U-251MG cells. Tumorigenicity of U-251MG-SC1 cells were higher than that of U-251MG cells. U-251MGSC1 cells exhibite d higher expression of CD44, SOX2, Nestin and A2B5 than U-251MG cells in vitro and in vivo. The expression of GFAP and NF-M was enhanced when the cells were treated with the conditioned medium of U-251MG cells indicating the potential of differentiation. Sphere forming ability was more efficient than that of U-251MG cells and was enhanced in the presence of hyaluronic acid, which enhanced the cell growth as well. U-251MGSC1 cells exhibited rapid growth tumor in nude mice and efficient metastatic ability in transmembrane assay when compared with U-251MG cells. As the result, we concluded U-251MGSC1 cell was a glioblastoma CSC line derived from the parental U-251MG cells. U-251MGSC1 cells will be a good tool to develop effective therapeutic agents against CSCs and to elucidate the properties of glioma derived CSCs and the mechanism of tumor development in brain.
Keywords: CD44; Cancer stem cell; GFAP; SOX2; glioblastoma; sphere formation.
AJCR Copyright © 2021.
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6
Am J Cancer Res
2021 Feb 1;11(2):530-545. eCollection 2021.
Degradation of BRD4 - a promising treatment approach not only for hematologic but also for solid cancer
Karin Bauer 1 2 3, Anna S Berghoff 4, Matthias Preusser 2 4, Gerwin Heller 2 4, Christoph C Zielinski 2 4, Peter Valent 1 2 3, Thomas W Grunt 1 2 4
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PMID: 33575085 PMCID: PMC7868748
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Abstract
Bromodomain (BRD) and extra-terminal (BET) proteins are epigenetic readers that regulate gene expression and promote cancer evolution. Pharmacological inactivation of BRD4 has recently been introduced as a promising anti-neoplastic approach that targets MYC oncogene expression. However, resistance against BRD4-targeting drugs has been described. We compared the efficacy of the small-molecule-type BET BRD inhibitor JQ1 with the recently developed BET protein degraders dBET1 and dBET6 in colon, breast, melanoma, ovarian, lung and prostate cancer cell lines. As determined by qPCR, all BRD4 targeting drugs dose-dependently decreased MYC expression, with dBET6 introducing the strongest downregulation of MYC. This correlated with the anti-proliferative activity of these drugs, which was at least one order of magnitude higher for dBET6 (IC50 0.001-0.5 µM) than for dBET1 or JQ1 (IC50 0.5-5 µM). Interestingly, when combined with commonly used cytotoxic therapeutics, dBET6 was found to promo te anti-neoplastic effects and to counteract chemoresistance in most cancer cell lines. Moreover, JQ1 and both BET degraders strongly downregulated baseline and interferon-gamma induced expression of the immune checkpoint molecule PD-L1 in all cancer cell lines. Together, our data suggest that dBET6 outperforms first-generation BRD4 targeting drugs like dBET1 and JQ1, and decreases chemoresistance and immune resistance of cancer.
Keywords: BET degrader; MYC; PD-L1; dBET6; solid tumor.
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Review Am J Cancer Res
2021 Feb 1;11(2):337-349. eCollection 2021.
Combination of NK-based immunotherapy and sorafenib against hepatocellular carcinoma
Jia Yang 1, Aydin Eresen 1, Alessandro Scotti 2 3, Kejia Cai 2 3, Zhuoli Zhang 1 4
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PMID: 33575075 PMCID: PMC7868752
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Abstract
Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver, which is considered the fourth leading cause of cancer-related death in the United States. Liver transplant and surgical resection are curative treatments for HCC, but only 10-15% of HCC patients are eligible candidates. The FDA-approved sorafenib is a multi-kinase inhibitor systemic therapy for advanced HCC that extends the overall survival by over 3 months when compared with placebo. Adoptive transfer of Natural Killer (NK) cells holds great promise for clinical cancer treatment. However, only limited clinical benefit has been achieved in cancer patients. Therefore, there is currently considerable interest in development of the combination of sorafenib and NK cells for the treatment of HCC patients. However, the mechanism of how sorafenib affects the function of NK cells remains to be comprehensively clarified. In this paper, we will discuss NK cell-based immunotherapies that are currently under preclinica l and clinical investigation and its potential combination with sorafenib for improving the survival of HCC patients.
Keywords: Natural killer cells; combination therapies; hepatocellular carcinoma; sorafenib.
AJCR Copyright © 2021.
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3 figures
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8
Am J Cancer Res
2021 Jan 1;11(1):61-78. eCollection 2021.
Radiation engenders converse migration and invasion in colorectal cancer cells through opposite modulation of ANXA2/AKT/GSK3β pathway
Han Pan 1, Yimeng Song 1, Hang Zhang 1, Yang Bai 1, Teruaki Konishi 2 3, Alisa Kobayashi 2 3, Chunlin Shao 1, Yan Pan 1
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PMID: 33520360 PMCID: PMC7840724
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Abstract
Radiation therapy is an effective non-surgical means to achieve local control for various solid tumors including colorectal cancer (CRC), but metastasis and recurrences after conventional radiotherapy remains a major obstacle in clinical practice, and the knowledge concerning the changes of metastatic potential after heavy ion radiation is still limited. This study investigated how radiation, including γ- and carbon ion radiation, would change the metastatic capacity of two CRC cell lines, HCT116 and DLD-1, and examined the underlying molecular mechanisms. We found that the migration and invasion was enhanced in DLD-1 cells but impaired in HCT116 cells in vitro and in vivo after radiation of γ-rays or carbons, and radiation induced epithelial mesenchymal transition (EMT) in DLD-1 cells but mesenchymal epithelial transition (MET) in HCT116 cells. The expression of snail, a key inducer of EMT, was significantly enhanced by inhibition of glycogen synthase kinase-3β (GSK3β) in both c ell lines, suggesting the modulation of snail was alike in the two CRC cell lines. However, radiation inactivated GSK3β through stimulating the phosphorylation of AKT and GSK3β at Ser473 and Ser9 in DLD-1 cells respectively, but activated GSK3β by decreasing the expression of pAKTSer473 and pGSK3βSer9 or increasing the phosphorylation of GSK3β at Tyr216 in HCT116 cells. Therefore, the above inverted motility changes was due to the opposite modulation of AKT/GSK3β signaling pathway by radiation, which was further verified in other type of cancer cell lines including MCF-7, U251 and A549 cells. Moreover, it was found that annexin A2 (ANAX2) directly bound with GSK3β and acted as a negative regulator of GSK3β upon radiation. Knocking-down ANXA2 gene reversed the enhanced migration of the irradiated DLD-1 cells and strengthened radiation-impaired migration of HCT116 cells. Collectively, this study reveals that the change of cellular motility after radiation is independent of rad iation type but is correlated with the inherent of cells.
Keywords: ANXA2/GSK3β; Colorectal cancer cells; EMT; migration and invasion; radiation.
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Am J Cancer Res
2021 Jan 1;11(1):123-137. eCollection 2021.
Hypoxia-induced lncRNA CASC9 enhances glycolysis and the epithelial-mesenchymal transition of pancreatic cancer by a positive feedback loop with AKT/HIF-1α signaling
Zhengle Zhang 1, Erhu Fang 2, Yuping Rong 1, Han Han 3, Qiong Gong 1, Yingyan Xiao 4, Hehe Li 5, Pei Mei 1, Hanjun Li 1, Zhongchao Zhu 1, Zhigang Tang 1, Jing Tao 1
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PMID: 33520364 PMCID: PMC7840708
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Abstract
Increasing evidence indicates the dysregulations and pivotal roles of lncRNAs in the development and progression of various cancers, including pancreatic cancer. Enhanced glycolytic flux and epithelial-to-mesenchymal transition (EMT) have been considered as important factors in driving the malignance of pancreatic cancer. Here, we sought to evaluate the biological role and involved mechanism of lncRNA CASC9 (CASC9) in pancreatic cancer. Our present study showed that CASC9 was upregulated in various pancreatic cancer cell lines. Loss- and gain-of function of CASC9 demonstrated its critical roles in promoting the glycolysis and EMT phenotypes of pancreatic cancer. Moreover, knockdown of CASC9 inhibited the tumorigenicity and metastasis in vivo. Additionally, our findings showed that hypoxia induced the expression of CASC9 and enhanced the binding of HIF-1α to its promoter. We also demonstrated that the positive feedback loop of CASC9 and the AKT/HIF-1α signaling cascade partially med iated this biological process. Altogether, our results suggest that CASC9 promotes the glycolysis and EMT of pancreatic cancer by a positive feedback loop with AKT/HIF-1α signaling, which is synergistically enhanced by the tumor hypoxic niche. Our study will provide potential therapeutic targets for treating pancreatic cancer.
Keywords: AKT; CASC9; EMT; HIF-1α; glycolysis; hypoxia; pancreatic cancer.
AJCR Copyright © 2021.
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10
Review Am J Cancer Res
2021 Jan 1;11(1):14-30. eCollection 2021.
Macropinocytosis: mechanism and targeted therapy in cancers
Feng Xiao 1 2, Jingying Li 3 2, Kai Huang 1 2, Xin Li 1 2, Yaping Xiong 4 2, Miaojing Wu 1 2, Lei Wu 5, Wei Kuang 5, Shigang Lv 1, Lei Wu 1 2, Xingen Zhu 1 2, Hua Guo 1 2
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PMID: 33520357 PMCID: PMC7840718
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Abstract
Macropinocytosis is a form of endocytosis which provides an effective way for non-selective uptakes of extracellular proteins, liquids, and particles. The endocytic process is initiated by the activation of the growth factors signaling pathways. After activation of the biochemical signal, the cell starts internalizing extracellular solutes and nutrients into the irregular endocytic vesicles, known as macropinosomes that deliver them into the lysosomes for degradation. Macropinocytosis plays an important role in the nutritional supply of cancer cells. Due to the rapid expansion of cancer cells and the abnormal vascular microenvironment, cancer cells are usually deprived of oxygen and nutrients. Therefore, they must transform their metabolism to survive and grow in this harsh microenvironment. To satisfy their energy needs, cancer cells enhance the activity of macropinocytosis. Therefore, this metabolic adaptation that is used by cancer cells can be exploited to develop new targeted ca ncer therapies. In this review, we discuss the molecular mechanism that actuates the process of macropinocytosis in a variety of cancers, and the novel anti-cancer therapeutics in targeting macropinocytosis.
Keywords: Macropinocytosis; cancer mechanism; growth factors; targeted cancer therapy.
AJCR Copyright © 2021.
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11
Review Am J Cancer Res
2021 Feb 1;11(2):318-336. eCollection 2021.
Clinical applicability of renin-angiotensin system inhibitors in cancer treatment
Huirong Jiang 1 2 3 4, Zongguang Tai 1 2 3, Zhongjian Chen 2, Quangang Zhu 2, Leilei Bao 1
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PMID: 33575074 PMCID: PMC7868760
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Abstract
The renin-angiotensin system (RAS) regulates physiological functions of the cardiovascular system, kidneys, and other tissues. Various in vivo and in vitro studies have shown that RAS plays a pivotal role in the development of malignant tumors, while several retrospective studies have confirmed that patients undergoing long-term RAS inhibitors (RASi) treatment have a lowered risk of cancer. Moreover, blocking RAS has been shown to inhibit tumor growth, metastasis, and angiogenesis in various experimental models of malignant tumors. Herein, we review the available RASi-related literature and provide an analysis using the scientific atlas software VOSviewer. We observed that recent studies have primarily focused on gene expression, tumor biology, and survival analysis. Through an in-depth data analysis from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx), we identified the impact of AGTR1, an essential component of RAS, on tumors, and we discuss the underlying biol ogical mechanism of RASi. Furthermore, we outline the research progress and potential use of RASi in tumor treatment. Overall, RASi may be a promising adjunct in cancer therapy.
Keywords: AGTR1; RAS inhibitors; Renin-angiotensin system; angiotensin receptor blockers; tumor.
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12
Am J Cancer Res
2021 Jan 1;11(1):236-250. eCollection 2021.
Nuclear translocation of the receptor tyrosine kinase c-MET reduces the treatment efficacies of olaparib and gemcitabine in pancreatic ductal adenocarcinoma cells
Yuan Gao 1 2, Mei-Kuang Chen 2, Yu-Yi Chu 2, Liuqing Yang 2, Dihua Yu 2, Yingbin Liu 1, Mien-Chie Hung 3 2 4
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PMID: 33520371 PMCID: PMC7840709
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that lack effective therapeutic strategies. The response rate of PDAC for treatment with gemcitabine, a current first-line chemotherapeutic for this tumor, is lower than 20%. Identifying key targetable molecules that mediate gemcitabine resistance and developing novel strategies for precision PDAC medicine are urgently needed. Most PDACs have either intratumoral hypoxia or high reactive oxygen species (ROS) production; cytotoxic chemotherapy can elevate ROS production in PDACs. Although excessive ROS production leads to oxidative damage of macromolecules such as DNA, pancreatic cancer cells can survive high DNA damage stress levels. Therefore, identifying molecular mechanisms of overcoming ROS-induced stress in pancreatic cancer cells is important for developing novel therapeutic strategies. ROS-induced DNA damage is predominantly repaired via poly (ADP-ribose) polymerase 1 (PARP1)-mediated DNA repair mechanisms. A recen t clinical trial reported that PARP inhibitors are effective in treating pancreatic patients carrying BRCA mutations. However, only less than 10% of pancreatic cancer patients bearing BRCA mutated tumors. Activation of the receptor tyrosine kinase c-MET positively correlates with poor prognosis for PDAC, and our previous study showed that nuclear c-MET can phosphorylate PARP1 at tyrosine 907 under ROS stimulation to promote DNA repair. As described herein, we proposed to expand PARP inhibitor-targeted therapy to more pancreatic cancer patients regardless of BRCA mutation status by combining olaparib, a PARP inhibitor, with c-MET inhibitors as we demonstrated in our previous studies in breast cancer. In this prospective study, we found that ROS-inducing chemotherapeutic drugs such as gemcitabine and doxorubicin stimulated nuclear accumulation of c-MET in BxPC-3 and L3.6pl pancreatic cancer cells. We further showed that combining a c-MET inhibitor with gemcitabine or a PARP inhibitor induced more DNA damage than monotherapy did. Moreover, we demonstrated the synergistic antitumor effects of c-MET inhibitors combined with a PARP inhibitor or gemcitabine in eliminating pancreatic cancer cells. These data suggested that accumulation of ROS in pancreatic cancer cells promotes nuclear localization of c-MET, resulting in resistance to both chemotherapy and PARP inhibitors. Our findings suggest that combining c-MET inhibitors with PARP inhibitors or gemcitabine is a novel, rational therapeutic strategy for advanced pancreatic cancer.
Keywords: DNA damage; PARP inhibitor; Pancreatic ductal adenocarcinoma; chemotherapy; precision medicine; reactive oxygen species; resistance; targeted therapy; tivantinib.
AJCR Copyright © 2021.
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13
Review Am J Cancer Res
2021 Jan 1;11(1):43-60. eCollection 2021.
Detection of carcinoma in serous effusions: a review
Min Li 1, Lanbo Zhao 1, Xue Zhou 1, Kailu Zhang 1, Panyue Yin 1, Shuhua Liu 2, Yuliang Zou 1, Qiling Li 1
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PMID: 33520359 PMCID: PMC7840719
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Abstract
A malignant serous effusion is one of the most common complications of advanced tumors, indicating a poor prognosis and having a profound impact on diagnosis, treatment, and prognosis. It is of great significance to identify benign and malignant effusions quickly and accurately. Both cellular and non-cellular components in the effusion can be employed for detection, diagnostic methods are necessary to obtain a definite diagnosis and more relevant information such as tumor classification. In this review, we focus on the comparison of several widespread cytological preparation methods, enrichment technology of exfoliated cells, and present tests for serous effusions, mainly including routine and special stains, immunocytochemistry, electron microscopy, enzyme-linked immunosorbent assay, flow cytometry, and molecular analysis.
Keywords: Serous effusions; cell enrichment procedures; cytological materials; molecular analysis; preparation methods.
AJCR Copyright © 2021.
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14
Review Am J Cancer Res
2021 Feb 1;11(2):301-317. eCollection 2021.
Unraveling the molecular mechanisms between inflammation and tumor angiogenesis
Wenwen Zhou 1, Longtao Yang 1, Lin Nie 2, Hui Lin 2
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PMID: 33575073 PMCID: PMC7868762
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Abstract
Inflammatory mediators in tumor microenvironment influence cancer occurrence, growth and metastasis through complex signaling networks. Excessive inflammation is closely associated with elevated cancer risk and mortality, in part through inflammation-induced angiogenesis. Mechanistically, multiple tumor-associated inflammatory cells increase the release and accumulation of various inflammatory products in cancerous sites. These products in turn activate tumor associated signaling cascades such as STAT3, NF-κB, PI3K/Akt and p38 MAPK, which mediate the recruitment of inflammatory cells and secretion of pro-inflammatory factors. More importantly, these events promote the secretion of various pro-angiogenesis factors from endothelial, tumor and inflammatory cells, which then drive malignancy in endothelial cells in a paracrine and/or autocrine manner. Its ultimate effect is to promote endothelial cell proliferation, migration, survival and tube formation, and to hence the formation of b lood vessels in tumors. This review describes the signaling network that connects the interaction between inflammation and cancer, especially those involved in inflammation-induced angiogenesis. This will reveal potential targets for the design of anti-inflammatory treatments and drugs that inhibites tumor growth and angiogenesis.
Keywords: Inflammation; endothelial cells; signal pathway; tumor angiogenesis.
AJCR Copyright © 2021.
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15
Am J Cancer Res
2021 Jan 1;11(1):251-263. eCollection 2021.
The N and C-termini of SPCA2 regulate differently Kv10.1 function: role in the collagen 1-induced breast cancer cell survival
Alban Girault 1, Marta Peretti 1, Mehdi Badaoui 1 2, Anaïs Hémon 1, Hamid Morjani 3, Halima Ouadid-Ahidouch 1
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PMID: 33520372 PMCID: PMC7840723
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Abstract
It's now clearly established that the tumor microenvironment participates to tumor development. Among the different actors contributing to these processes, ion channels, located at the cancer cell surface, play a major role. We recently demonstrated that the association of Kv10.1, Orai1 and SPCA2 is crucial to promote the collagen-induced survival of MCF-7 breast cancer cells. By using siRNA directed against SPCA2, we shown that this protein is involved in the regulation of the activity, the expression and the sub-cellular localization of Kv10.1. In addition, it has been demonstrated that SPCA2 is involved in SICE in MCF-7 cells and that the N- and the C-terminal parts of this protein are necessary to interact and to produce Ca2+ entry. However, no information is available about the necessary SPCA2's important region to regulate Kv10.1. The aim of our work is to evaluate how SPCA2 could interact with Kv10.1 channel to induce survival promotion. By using different SPCA2 mutants, we ev aluate the role of the N- and C-terminal sections on the expression and the activity of Kv10.1 channels. In addition, we analyzed the impact of these deletions on the collagen 1-induced cell survival. Our results bring out new information about the regulation of Kv10.1 channel through SPCA2. More specifically how the N- and C-terminus of this Ca2+ transporter regulate Kv10.1 expression, trafficking, and function suggesting new opportunities to target Kv10.1 channels in cancer progression.
Keywords: Kv10.1; SPCA2; breast cancer cells; orai1; tumor microenvironment.
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16
Am J Cancer Res
2021 Feb 1;11(2):416-440. eCollection 2021.
YEATS4 is associated with poor prognosis and promotes epithelial-to-mesenchymal transition and metastasis by regulating ZEB1 expression in breast cancer
Yang Li 1, Lei Li 1, Junyi Wu 1, Jun Qin 1, Xueming Dai 1, Tao Jin 1, Junming Xu 1
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PMID: 33575079 PMCID: PMC7868763
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Abstract
YEATS domain-containing protein 4 (YEATS4) is implicated in several oncogenic signaling pathways, and its expression is involved in various types of cancer; regardless, the pathophysiologic effects of YEATS4 on breast cancer remain unclear. This study finds that YEATS4 is increasingly expressed with breast cancer progression, and its expression is related to poor outcome and distant metastasis. YEATS4 overexpression in breast cancer cells strengthens their malignant characteristics in vitro and in vivo, particularly inducing epithelial-to-mesenchymal transition (EMT) and consequently, metastatic capability in breast cancer cells. By contrast, deleting YEATS4 in breast cancer cells with high-grade malignancy reduced these characteristics. With regard to the molecular mechanism, YEATS4 mediates histone H3K27ac at specific sites of the ZEB1 promoter to regulate its expression at the transcription level. Depleting ZEB1 blocks YEATS4-induced EMT, migration, invasion, and metastasis. YEATS 4 expression is also positively correlated with ZEB1 expression in patients with breast cancer. Co-expression of YEATS4 and ZEB1 correlates with the shortest distant metastasis-free period. Taken together, our data reveal the critical role of YEATS4 in the progression and metastasis of breast cancer, as well as support YEATS4 as a potential therapeutic target and prognostic biomarker for breast cancer.
Keywords: EMT; YEATS4; ZEB1; breast cancer; metastasis.
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17
Am J Cancer Res
2021 Jan 1;11(1):181-199. eCollection 2021.
Tumor-intrinsic and -extrinsic (immune) gene signatures robustly predict overall survival and treatment response in high grade serous ovarian cancer patients
David P Mysona 1 2, Lynn Tran 3, Shan Bai 3, Bruno Dos Santos 2, Sharad Ghamande 4, John Chan 5, Jin-Xiong She 3 4
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PMID: 33520368 PMCID: PMC7840710
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Abstract
In the present study, we developed a transcriptomic signature capable of predicting prognosis and response to primary therapy in high grade serous ovarian cancer (HGSOC). Proportional hazard analysis was performed on individual genes in the TCGA RNAseq data set containing 229 HGSOC patients. Ridge regression analysis was performed to select genes and develop multigenic models. Survival analysis identified 120 genes whose expression levels were associated with overall survival (OS) (HR = 1.49-2.46 or HR = 0.48-0.63). Ridge regression modeling selected 38 of the 120 genes for development of the final Ridge regression models. The consensus model based on plurality voting by 68 individual Ridge regression models classified 102 (45%) as low, 23 (10%) as moderate and 104 patients (45%) as high risk. The median OS was 31 months (HR = 7.63, 95% CI = 4.85-12.0, P < 1.0-10) and 77 months (HR = ref) in the high and low risk groups, respectively. The gene signature had two components: intrinsic (proliferation, metastasis, autophagy) and extrinsic (immune evasion). Moderate/high risk patients had more partial and non-responses to primary therapy than low risk patients (odds ratio = 4.54, P < 0.001). We concluded that the overall survival and response to primary therapy in ovarian cancer is best assessed using a combination of gene signatures. A combination of genes which combines both tumor intrinsic and extrinsic functions has the best prediction. Validation studies are warranted in the future.
Keywords: High grade serous ovarian cancer; chemotherapy resistance; gene signature; immune evasion; machine learning; prognosis.
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18
Am J Cancer Res
2021 Feb 1;11(2):576-589. eCollection 2021.
Deep learning radiomics model accurately predicts hepatocellular carcinoma occurrence in chronic hepatitis B patients: a five-year follow-up
Jieyang Jin 1 2, Zhao Yao 3, Ting Zhang 1 2, Jie Zeng 1 2, Lili Wu 1 2, Manli Wu 1 2, Jinfen Wang 1 2, Yuanyuan Wang 3 4, Jinhua Yu 3 4, Rongqin Zheng 1 2
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PMID: 33575088 PMCID: PMC7868753
Free PMC article
Abstract
An early and accurate prediction of hepatocellular carcinoma (HCC) is beneficial for individualized treatment and follow-up of chronic hepatitis B (CHB) patients. We aimed to establish a prediction model for HCC by radiomics analysis in CHB patients and compare performance with liver stiffness measurement (LSM) and other clinical prognostic scores. Initially, 1215 patients were included and finally 434 CHB patients with 5-year follow-up were enrolled, 96.3% of them underwent liver biopsy. Deep learning radiomics analysis was performed on 2170 two-dimensional shear wave elastography (2D-SWE) and corresponding B-mode ultrasound (US) images. These high-throughput imaging features were also combined with low-dimensional serological clinical data by deep learning radiomics to establish different HCC prediction models and to overcome challenges of an unbalanced sample. The best model which is simple with high accuracy was selected. Prediction performance of the selected model was compared with LSM and other clinical prognostic scores. During 5-year follow-up, 32 (7.4%) of 434 patients developed HCC. The best prediction model was HCC-R, which included 2D-SWE and B-mode US images, sex and age. This model showed a high predictive value with areas under the receiver operating characteristic curve (AUCs) of 0.981, 0.942 and 0.900 in training, validation and testing cohorts for predicting 5-year prognosis of HCC. These predictive values were significantly higher than that of LSM (AUC: 0.676~0.784, p < 0.05) and better than that of other clinical prognostic scores (AUC: 0.544~0.869). HCC-R radiomics model based on 2D-SWE and B-mode US images, sex and age comprehensively reflected biomechanical and morphological information of patients and can accurately predict HCC occurrence; thus, this model has great value for treatment and follow-up of CHB patients.
Keywords: Radiomics; elastography; hepatocellular carcinoma; prediction; ultrasound.
AJCR Copyright © 2021.
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None.
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19
Am J Cancer Res
2021 Jan 1;11(1):200-214. eCollection 2021.
Cinobufagin suppresses colorectal cancer growth via STAT3 pathway inhibition
Ying Bai 1 2, Xuye Wang 1 3, Mengsi Cai 1 2, Chunbo Ma 1 2, Youqun Xiang 2, Wanle Hu 4, Bin Zhou 4, Chengguang Zhao 1 2 3, Xuanxuan Dai 2, Xiaokun Li 1 3, Haiyang Zhao 1
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PMID: 33520369 PMCID: PMC7840714
Free PMC article
Abstract
Colorectal cancer (CRC) has become one of the most common types of cancer with the highest morbidity and mortality rates globally. Cinobufagin, a natural product extracted from toad venom and a major active ingredient in cinobufotalin, exhibits high antitumor activity. Here, we investigated the in vitro and in vivo antitumor activities of cinobufagin and explored the underlying mechanisms in CRC. Cinobufagin could inhibit proliferation, migration, invasion and promote apoptosis of HCT116, RKO, and SW480 cells in vitro. Mechanistically, cinobufagin simultaneously suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and blocked the interleukin-6 (IL6)-induced nuclear translocation of STAT3. IL6 activated the STAT3 pathway, subsequently inducing epithelial-mesenchymal transition (EMT). Furthermore, cinobufagin suppressed EMT in CRC by inhibiting the STAT3 pathway. Animal experiments clearly showed that cinobufagin could reduce tumor growth. Cinobu fagin may be used clinically as a novel STAT3 inhibitor for CRC adjuvant therapy.
Keywords: Cinobufagin; EMT; STAT3; colorectal cancer; inhibitor.
AJCR Copyright © 2021.
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None.
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Am J Cancer Res
2021 Jan 1;11(1):92-107. eCollection 2021.
Ese-3 contributes to colon cancer progression by downregulating EHD2 and transactivating INPP4B
Junqiang Li 1, Jing Yang 1, Lei Hua 1, Ronglin Wang 1, Hong Li 1, Chao Zhang 1, Haihua Zhang 2, Shanshan Li 1, Liaoliao Zhu 1, Haichuan Su 1
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PMID: 33520362 PMCID: PMC7840712
Free PMC article
Abstract
Epithelium-specific Ets protein 3 (Ese-3), a member of the Ets family of transcription factors, plays an important role in the development of cancers. However, little is known concerning its role in colon cancer (CC). In this study, we demonstrate that the expression of Ese-3 is upregulated in CC tissues and elevated Ese-3 expression is relationship with advanced T stage (P=0.037) and poor disease-free survival (DFS, P=0.044). Univariate and multivariate cox regression analyses show that Ese-3 expression may be an independent prognostic value for CC patients. Moreover, Ese-3 knockdown suppresses CC cell proliferation in vitro and in vivo, while Ese-3 overexpression has the opposite result. Further, we first demonstrate that EHD2 and INPP4B are the downstream genes of Ese-3. Subsequent investigation find that EHD2 is downregulated in CC tissues and knockdown of EHD2 significantly increase CC cell proliferation in vitro and vivo. Our findings reveal that Ese-3 promotes CC cell prolifer ation by downregulating EHD2 and transactivating INPP4B, and targeting the pathway may be a promising therapeutic target for CC patients.
Keywords: EHD2; Ese-3; INPP4B; colon cancer; proliferation.
AJCR Copyright © 2021.
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None.
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