Cancer Letters

Interference with the bromodomain epigenome readers drives p21 expression and tumor senescence Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Liana P. Webber, Veronica Q. Yujra, Pablo A. Vargas, Manoela D. Martins, Cristiane H. Squarize, Rogerio M. Castilho Abstract Head and neck cancer (HNSCC) are one of the most common solid malignancies of the world, being responsible for over 350,000 deaths every year. Much of the complications in managing and treating HNSCC advent from the complex genetic and epigenetic landscape of the disease. Emerging information has shown promising results in targeting BRD4, an epigenetic regulator bromodomain that functions as a scaffold for transcription factors at promoters and super-enhancers. Here we show that by disrupting the interaction between BRD4 and histones using the bromodomain inhibitor JQ1, HNSCC cells undergo cell growth arrest followed by cellular senescence. Mechanistically, JQ1 negatively impacted the phosphorylation levels of SIRT1 along with the acetylation levels of mutant p53 (active). In vivo administration of JQ1 resulted in disruption of HNSCC growth along with the activation of cellular senescence, observed by the accumulation of DNA double-strand breaks, p16ink4, accumulation of senescence-associated beta-galactosidase, and loss of phosphorylated Sirt1ser47. Furthermore, we also demonstrate that JQ1 was efficient in reducing the population of cancer stem cells from HNSCC xenografts.

Improved anti-tumor efficacy of paclitaxel in combination with MicroRNA-125b-based tumor-associated macrophage repolarization in epithelial ovarian cancer Publication date: 1 October 2019 Source: Cancer Letters, Volume 461 Author(s): Neha N. Parayath, Srujan Kumar Gandham, Fraser Leslie, Mansoor M. Amiji Abstract In epithelial ovarian cancers, the presence of tumor-associated macrophages (TAMs) is well correlated with the poor disease outcomes. TAMs are know to suppress the immune system, induce pro-tumoral functions and inhibit anti-tumor responses associated with chemotherapy. In this study, we have evaluated the synergistic efficacy of TAM repolarization and intraperitoneal paclitaxel in epithelial ovarian cancers. We demonstrate that hyaluronic acid-based nanoparticles encapsulating miR-125b (HA-PEI-miR-125b) can specifically target TAMs in the peritoneal cavity of a syngeneic ID8-VEGF ovarian cancer mouse model and can repolarize macrophages to an immune-activating phenotype. These HA-PEI-miR-125b nanoparticles in combination with intraperitoneal paclitaxel can enhance the anti-tumor efficacy of paclitaxel during the later stages of disease progression as seen by the significant reduction in the ascitic fluid and peritoneal VEGF levels. Furthermore, these HA-PEI-miR-125b nanoparticles do not induce systemic toxicity and thus warrant a further evaluation in the clinical setting.

Tumor-derived extracellular vesicles in breast cancer: From bench to bedside Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Hong-Xia Wang, Olivier Gires Abstract Tumor-derived extracellular vesicles (TEVs) released from various tumor cell types comprise endosome-derived exosomes and microvesicles (MVs), which originate from plasma membrane budding. TEVs incorporate a myriad of biomolecules such as proteins, DNAs, metabolites and microRNAs, which can be transferred from cell-to-cell. Besides their role in the disposal of biomolecules, TEVs serve to orchestrate fundamental processes of normal and malignant development, including breast cancer (BC). As such, TEVs are important constituents of the tumor microenvironment (TME) that act as communication shuttles through transduction of encapsulated molecular cargos from a parent to a recipient cell and through direct interaction with target cells. Emerging evidence suggests that TEVs support BC development and disease progression by fostering invasion, angiogenesis, pre-metastatic niche preparation, escape from immune surveillance, and induction of resistance to treatment. Although there is a long way to go in order to translate the current knowledge into actual clinical applications, TEVs represent promising candidates for diagnostic biomarkers, therapeutic carriers and targets. In the present review, we will summarize the current knowledge on TEVs in BC.

Coming of a precision era of the staging systems for intrahepatic cholangiocarcinoma? Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Zhangjun Cheng, Zhengqing Lei, Feng Shen Abstract Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Appropriate treatment of this aggressive and heterogeneous cancer requires accurate staging and prognostic stratification, as does patient selection for clinical trials. Over the past two decades, several staging systems and prognostic models for ICC have been developed. Most include independent prognostic factors such as tumor extent, clinical parameters and histopathological features and are inaccurate. Accumulating findings offer new insights into the genetic and molecular basis of ICC progression. Hence, staging systems and prognostic models that incorporate in clinicalpathological factors, molecular and genomic information, and tumor biomarkers, and hence more accurately estimate prognosis, will become a reality. This review summarizes the current staging systems and prognostic models for ICC and highlights the need to establish more precise and personalized systems and models that incorporate tumor biologic factors.

Targeted therapy for hepatocellular carcinoma: Challenges and opportunities Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Shuzhen Chen, Qiqi Cao, Wen Wen, Hongyang Wang Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.

hsa_circ_0091570 acts as a ceRNA to suppress hepatocellular cancer progression by sponging hsa-miR-1307 Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Yu-Gang Wang, Tao Wang, Min Ding, Shi-Hao Xiang, Min Shi, Bo Zhai Abstract Alterations in circular RNA (circRNA) expression have a vital impact on the biological processes in cancer. Moreover, the expression pattern and roles of circRNAs in hepatocellular cancer (HCC) remain unclear. This study performed qRT-PCR to determine the regulated circRNAs in HCC tissues and cell lines. CCK8, 5-ethynyl-2′-deoxyuridine (EdU) assay, colony formation, cell cycle assay, apoptotic assay, transwell, and wound healing assay were conducted to assess the function of hsa_circ_0091570 or miR-1307 on cell proliferation, apoptosis, and migration in vitro. Mouse xenograft models were used to measure the functions of hsa_circ_0091570 in vivo. The decreased expression of hsa_circ_0091570 was associated with the pathological staging of HCC patients. Furthermore, inhibition of hsa_circ_0091570 promoted cell proliferation and migration, blocked cell apoptosis in HCC cell lines, and promoted tumor growth in the mouse xenograft model. RNA immunoprecipitation assay verified the interaction of hsa_circ_0091570 and miR-1307. The miR-1307 inhibitor inhibited the function induced by hsa_circ_0091570 siRNA. Overall, hsa_circ_0091570 sponge miR-1307 as a ceRNA and regulate ISM1 expression by exerting functional roles in HCC.

Piplartine suppresses proliferation and invasion of hepatocellular carcinoma by LINC01391-modulated Wnt/β-catenin pathway inactivation through ICAT Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Xiaoxi Fan, Jingjing Song, Zhongwei Zhao, Minjiang Chen, Jianfei Tu, Chenying Lu, Fazong Wu, Dengke Zhang, Qiaoyou Weng, Liyun Zheng, Min Xu, Jiansong Ji Abstract Although piplartine is regarded as an anticancer agent, the relationship between long noncoding RNAs (lncRNAs), which are involved in various diseases (e.g., tumors) and piplartine in hepatocellular carcinoma (HCC) remains unclear. We identified LINC01391 using microarray analysis and validated its expression by qRT-PCR. Functional assays were applied to evaluate the biological effects of LINC01391 and inhibitory of β-catenin and T-cell factor (ICAT) on HepG2 and SMMC-7721 cells. The binding relationship between LINC01391 and ICAT was determined by RNA pull-down and RNA immunoprecipitation (RIP). Results showed that piplartine attenuated cell proliferation and invasion but promoted cell apoptosis. Upregulation of LINC01391 induced by piplartine inhibited HCC cell proliferation, invasion in vitro, and tumor growth in vivo. LINC01391 interacted with ICAT and promoted its inhibitory effect on the Wnt/β-catenin pathway, as enhanced interaction between β-catenin and ICAT, and dampened interaction of β-catenin and TCF/LEF were induced by overexpression of LINC01391. Knockdown of ICAT also promoted cell proliferation in vitro and tumor growth in vivo. Our study supported a role for piplartine and LINC01391 in HCC treatment. We found that LINC01391 inhibited the Wnt/β-catenin pathway and suppressed tumor growth via ICAT.

Featuring the Guest Editor Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Shuai Jiang

CircNR3C1 inhibits proliferation of bladder cancer cells by sponging miR-27a-3p and downregulating cyclin D1 expression Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Fuxin Zheng, Miao Wang, Yawei Li, Chao Huang, Dan Tao, Fei Xie, Hui Zhang, Jiayin Sun, Chuanhua Zhang, Chaohui Gu, Zhendi Wang, Guosong Jiang Abstract Accumulating evidences suggest that circular RNAs play vital roles in human cancers. Previously, we found that circHIPK3 suppressed invasion of bladder cancer cells via sponging miR-558 and downregulating heparanase expression. In this study, we discovered that a circular RNA derived from NR3C1 (circNR3C1) was downregulated in bladder cancer tissues and cell lines according to RNA-Seq data and qRT-PCR analysis. Functionally, we found that overexpression of circNR3C1 could significantly inhibit cell cycle progression and proliferation of bladder cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistically, we demonstrated that circNR3C1 possessed four targeting sites of miR-27a-3p and could effectively sponge miR-27a-3p to suppress the expression of cyclin D1. Furthermore, we revealed that miR-27a-3p functioned as an oncogene through interacting with 5′UTR of cyclin D1 to enhance its expression, which led to promote cell cycle progression and proliferation in bladder cancer cells. Conclusively, our findings further confirm the hypothesis that circRNAs function as “microRNA sponges”, and our data suggest that circNR3C1 and miR-27a-3p would be potential therapeutic targets for bladder cancer treatment.

A recombinant measles virus vaccine strain rMV-Hu191 has oncolytic effect against human gastric cancer by inducing apoptotic cell death requiring integrity of lipid raft microdomains Publication date: 28 September 2019 Source: Cancer Letters, Volume 460 Author(s): Yao Lv, Duo Zhou, Xiao-qiang Hao, Meng-ying Zhu, Chu-di Zhang, Dong-ming Zhou, Jin-hu Wang, Rong-xian Liu, Yi-long Wang, Wei-zhong Gu, Hong-qiang Shen, Xi Chen, Zheng-yan Zhao Abstract Live-attenuated strain of measles virus (MV) has oncolytic effect. In this study, the antitumor effect of rMV-Hu191, a recombinant Chinese Hu191 MV generated in our laboratory by efficient reverse genetics system, was evaluated in gastric cancer (GC). From our data, rMV-Hu191 induced cytopathic effects and inhibited tumor proliferation both in vitro and in vivo by inducing caspase-dependent apoptosis. In mice bearing GC xenografts, tumor size was reduced and survival was prolonged significantly after intratumoral injections of rMV-Hu191. Furthermore, lipid rafts, a type of membrane microdomain with specific lipid compositions, played an important role in facilitating entry of rMV-Hu191. Integrity of lipid rafts was required for successful viral infection as well as subsequent cell apoptosis, but was not required for viral binding and replication. CD46, a MV membrane receptor, was found to be partially localized in lipid rafts microdomains. This is the first study to demonstrate that Chinese Hu191 MV vaccine strain could be used as a potentially effective therapeutic agent in GC treatment. As part of the underlying cellular mechanism, the integrity of lipid rafts is required for viral entry and to exercise the oncolytic effect.