YY1 inhibits the migration and invasion of pancreatic ductal adenocarcinoma by downregulating the FER/STAT3/MMP2 signaling pathway Publication date: 28 October 2019 Source: Cancer Letters, Volume 463 Author(s): Qun Chen, Jing-Jing Zhang, Wan-Li Ge, Lei Chen, Hao Yuan, Ling-Dong Meng, Xu-Min Huang, Peng Shen, Yi Miao, Kui-Rong Jiang Abstract Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and a high mortality rate. The transcription factor YY1 acts as an inhibitor of many types of tumors. We found that YY1 knockdown promoted the invasion and migration of PANC-1 and BxPC-3 cells; FER knockdown partially restored the promotion of pancreatic cancer caused by YY1 knockdown. In vivo experiments yielded the same results. According to luciferase reporter gene, electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays, YY1 directly binds to the FER promoter region. Moreover, higher level FER expression results in a worse TNM stage and prognosis for patients with PDAC. Furthermore, by downregulating FER, YY1 inhibits the formation of the STAT3-MMP2 complex, thereby suppressing expression of MMP2 and ultimately inhibiting the migration and invasion of pancreatic cancer. Our study demonstrates that the YY1/FER/STAT3/MMP2 axis is associated with the progression of pancreatic cancer and may provide a new therapeutic target for the treatment of pancreatic cancer. Graphical abstract

Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling Publication date: 28 October 2019 Source: Cancer Letters, Volume 463 Author(s): Guoxu Fang, Peilin Zhang, Jingfeng Liu, Xu Zhang, Xiangjie Zhu, Rong Li, Hongyang Wang Abstract Glycogen synthase kinase-3 beta (GSK-3β) has been shown to play a critical role in the development of many cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. Deregulating cellular energetics is a signature hallmark of cancer, therefore modulating cancer metabolism has become an attractive anti-cancer approach in recent years. As a key enzyme in glucose metabolism, understanding the role of GSK-3β in cancer metabolic process may facilitate the development of effective therapeutic approach for HCC. In this study, we showed that inhibition of GSK-3β led to diminished viability, metastasis and tumorigenicity in HCC cells. Suppression of GSK-3β activity also reduced glucose consumption, lactate production and adenosine triphosphate (ATP) levels in HCC cells. The decreased extracellular acidification rate (ECAR) and down-regulated key enzymes on the glycolysis pathway by GSK3β inhibition demonstrated that GSK-3β was involved in glycolysis process of HCC. Mechanistically, the metabolic change and anti-cancer effect by GSK-3β inhibition was achieved mainly through activation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, which negatively affected glycolysis and cell proliferation. The results from primary HCC cells and from in vivo nude mice model confirmed our observations. Our study results indicated that GSK-3β may become a promising therapeutic target for HCC.

Deacetylation of β-catenin by SIRT1 regulates self-renewal and oncogenesis of liver cancer stem cells Publication date: 28 October 2019 Source: Cancer Letters, Volume 463 Author(s): Xuejiao Chen, Hongbo Huan, Chungang Liu, Yongli Luo, Junjie Shen, Yue Zhuo, Zhixin Zhang, Cheng Qian Abstract Hepatocellular carcinoma (HCC) is a highly malignant liver tumor. The presence of cancer stem cells (CSCs) figures prominently in tumor invasion, therapeutic resistance and tumor recurrence resulting in poor outcome and limited therapeutic options. Wnt/β-catenin signaling is essential for cancer stem cell regulation and tumorigenesis in HCC, but its molecular mechanisms are not fully understood. Here, we demonstrate that β-catenin is overexpressed in liver CSCs, and its expression level is positively correlated with SIRT1 in HCC specimens. SIRT1 regulates the protein stability of β-catenin, thereby affecting the transcriptional activity of Wnt/β-catenin signaling in liver CSCs. Mechanistically, we show that nuclear accumulation of β-catenin results from deacetylation mediated by SIRT1. Further, nuclear β-catenin promotes the transcription of Nanog to help maintain self-renewal of liver CSCs. Taken together, our findings indicate that the deacetylation of β-catenin by SIRT1 represents a critical mechanism for regulating liver CSCs self-renewal and tumorigenesis. It provides an improved understanding of molecular mechanisms underlying β-catenin activation and tumorigenesis in HCC.

Connecting cancer relapse with senescence Publication date: 28 October 2019 Source: Cancer Letters, Volume 463 Author(s): Olivier Pluquet, Corinne Abbadie, Olivier Coqueret Abstract Many cancers respond to initial treatment but most of them relapse due to the persistence of dormant tumor cells. Determining the exact nature of the dormant state is crucial to develop therapies aiming to eradicate the dormant cells. Here, we argue that therapy-induced senescence of cancer cells could be an alternative form of dormancy.

Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication Publication date: 28 October 2019 Source: Cancer Letters, Volume 463 Author(s): Federica Monaco, Simona Gaetani, Federica Alessandrini, Adriano Tagliabracci, Massimo Bracci, Matteo Valentino, Jiri Neuzil, Monica Amati, Massimo Bovenzi, Marco Tomasetti, Lory Santarelli Abstract MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR−126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM. Graphical abstract

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Xiaotao Jiang, Jiang Xu, Mingfeng Liu, Hui Xing, Zhiming Wang, Lei Huang, Andrew L. Mellor, Wei Wang, Sha Wu Abstract Cancer immunotherapy is a new and promising option for cancer treatment. Unlike traditional chemo- and radiotherapy, immunotherapy actives host immune system to attack malignancies, and this potentially offers long-term protection from recurrence with less toxicity in comparison to conventional chemo- and radiation therapy. In adoptive CD8+ T cell therapy (ACT), large numbers of tumor-specific T cells are sourced from patients and expanded in vitro and infused back to patients. T cells can be expanded from naturally-induced tumor-specific CD8+ T cells isolated from tumor infiltrating lymphocytes (TIL) or genetically-modified autologous circulating CD8+ T cells. The engineered T cells expressed tumor-specific antigen receptors including chimeric antigen receptors (CARs) and T cell receptors (TCRs), prepared from cultured B and T cell clones, respectively. The most successful ACT, anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy directed against B cell lymphoma, is already approved for use based on evidence of efficacy. Efficacy of solid tumors is not yet forthcoming. This review summarizes current technology developments using ACT in clinical trials. In this review, differences between various ACT approaches are discussed. Furthermore, resistance factors in the tumor microenvironment are also considered, as are immune related adverse effects, critical clinic monitoring parameters and potential mitigation approaches.

YAP1-mediated pancreatic stellate cell activation inhibits pancreatic cancer cell proliferation Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Ying Xiao, Hui Zhang, Qiang Ma, Rui Huang, Junliang Lu, Xiaolong Liang, Xuguang Liu, Zhiwen Zhang, Lianyuan Yu, Junyi Pang, Liangrui Zhou, Tonghua Liu, Huanwen Wu, Zhiyong Liang Abstract Pancreatic stellate cells (PSCs) are activated in pancreatic ductal adenocarcinoma (PDAC) and are responsible for dense desmoplastic stroma. Yes-associated protein 1 (YAP1) can induce cancer-associated fibroblast activation in liver and breast tumors, but its effect on PSCs is unknown. In the present study, we determined that YAP1 was highly expressed in the nuclei of PDAC-derived activated PSCs. RNAi-mediated or pharmacological inhibition of YAP1 led to PSC deactivation. In addition, YAP1 stimulated the expression of secreted protein acidic and cysteine rich (SPARC) in PSCs, which was inhibited by RUNX1. SPARC secreted from PSCs inhibited pancreatic cancer cell (PCC) proliferation. High expression of nuclear YAP1 in tumor stroma was significantly correlated with SPARC expression and fibrosis degree in human PDAC tissues. Our study revealed a critical role for YAP1 in the regulation of PSC activation and paracrine signaling. Our findings provide insights into a novel rationale for targeting YAP1 to reprogram the PDAC microenvironment.

The Ig superfamily protein PTGFRN coordinates survival signaling in glioblastoma multiforme Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Brittany Aguila, Adina Brett Morris, Raffaella Spina, Eli Bar, Julie Schraner, Robert Vinkler, Jason W. Sohn, Scott M. Welford Abstract Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a median survival of approximately 14 months. Despite aggressive treatment of surgical resection, chemotherapy and radiation therapy, only 3–5% of GBM patients survive more than 3 years. Contributing to this poor therapeutic response, it is believed that GBM contains both intrinsic and acquired mechanisms of resistance, including resistance to radiation therapy. In order to define novel mediators of radiation resistance, we conducted a functional knockdown screen, and identified the immunoglobulin superfamily protein, PTGFRN. In GBM, PTGFRN is found to be overexpressed and to correlate with poor survival. Reducing PTGFRN expression radiosensitizes GBM cells and potently decreases the rate of cell proliferation and tumor growth. Further, PTGFRN inhibition results in significant reduction of PI3K p110β and phosphorylated AKT, due to instability of p110β. Additionally, PTGFRN inhibition decreases nuclear p110β leading to decreased DNA damage sensing and DNA damage repair. Therefore overexpression of PTGFRN in glioblastoma promotes AKT-driven survival signaling and tumor growth, as well as increased DNA repair signaling. These findings suggest PTGFRN is a potential signaling hub for aggressiveness in GBM.

IL-10 knockdown with siRNA enhances the efficacy of Doxorubicin chemotherapy in EBV-positive tumors by inducing lytic cycle via PI3K/p38 MAPK/NF-kB pathway Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Li Gao, Haige Han, Honglei Wang, Li Cao, Wen-hai Feng Abstract High levels of IL-10 expression in Epstein–Barr virus (EBV) associated tumors have been reported and it is likely to be important for maintaining EBV latency and EBV-associated tumors. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. Here, we found that knockdown of IL-10 induced EBV lytic replication. Subsequently, we demonstrated that IL-10 knockdown activated BZLF1 promoter through PI3K-p38 MAPK-NF-κB signaling pathway. Interestingly, we verified that VEGF-A was required for IL-10 knockdown to activate PI3K signaling and the accompanying EBV lytic induction. Exogenous recombinant human VEGF-A induced PI3K activation and EBV lytic infection, and inhibition of VEGF-A signaling prevented the PI3K/AKT phosphorylation and EBV reactivation responded to IL-10 knockdown. Most importantly, IL-10 knockdown synergized with chemotherapeutic agent Doxorubicin to kill EBV associated tumor cells in vitro and repress EBV-positive tumor growth in vivo. Our results suggest that inhibition of IL-10 has the potential to serve as a new supplemental strategy for the treatment of EBV-associated tumors.

Induction of endoplasmic reticulum stress and inhibition of colon carcinogenesis by the anti-helmintic drug rafoxanide Publication date: 10 October 2019 Source: Cancer Letters, Volume 462 Author(s): Federica Laudisi, Antonio Di Grazia, Veronica De Simone, Fabio Cherubini, Alfredo Colantoni, Angela Ortenzi, Eleonora Franzè, Vincenzo Dinallo, Davide Di Fusco, Ivan Monteleone, Eric R. Fearon, Giovanni Monteleone, Carmine Stolfi Abstract Colorectal cancer (CRC) remains one of the leading causes of mortality worldwide. Drug repositioning is a promising approach for new cancer therapies, as it provides the opportunity to rapidly advance potentially promising agents into clinical trials. The FDA-approved anti-helminthic drug rafoxanide was recently reported to antagonize the oncogenic function of the BRAF V600E mutant protein, commonly found in CRCs, as well as to inhibit the proliferation of skin cancer cells. These observations prompted us to investigate the potential anti-cancer effects of rafoxanide in CRC models. We found rafoxanide inhibited proliferation in CRC cells, but not in normal colonic epithelial cells. Rafoxanide's anti-proliferative action was associated with marked reduction in cyclin D1 protein levels and accumulation of cells in the G0/G1 phase. These effects relied on selective induction of the endoplasmic reticulum stress (ERS) response in CRC cells and were followed by caspase-dependent cell death. Systemic administration of rafoxanide to Apcmin/+ mice induced to develop CRCs caused ERS activation, proliferation inhibition and apoptosis induction in the neoplastic cells. Collectively, our data suggest rafoxanide might be repurposed as an anti-cancer drug for the treatment of CRC.