Notes

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While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their functions and the underlying molecular mechanisms in cancers, particularly in estrogen receptor alpha (ERα)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) in ERα-positive breast cancers due to its high expression and the associated poor prognosis. Methods ChIP-seq and RNA-seq were employed to identify the chromatin-binding landscape and transcriptional targets of CARM1, respectively, in the presence of estrogen in ERα-positive MCF7 breast cancer cells. High-resolution mass spectrometry analysis of enriched peptides from anti-monomethyl- and anti-asymmetric dimethyl-arginine antibodies in SILAC labeled wild-type and CARM1 knockout cells were performed to globally map CARM1 methylation substrates. Cell viability was measured bound active enhancers to activate estrogen/ERα-target genes. In consistent with its critical role in estrogen/ERα-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERα-positive breast cancer cells in vitro and tumor growth in mice. Conclusions our study uncovered a "hypermethylation" strategy utilized by enhancer-bound CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment. © The author(s).Reactive oxygen species (ROS) play a crucial role in cancer formation and development, especially cancer metastasis. However, lack of a precise tool, which could accurately distinguish specific types of ROS, restricts an in-depth study of ROS in cancer development and progression. click here Herein, we designed smart and versatile fluorescent Ag nanoclusters (AgNCs) for sensitive and selective detection of different species of ROS in cells and tissues. Methods Firstly, dual-emission fluorescent AgNCs was synthesized by using bovine serum albumin (BSA) to sense different types of ROS (H2O2, O2•-, •OH). The responsiveness of the AgNCs to different species of ROS was explored by fluorescence spectrum, hydrodynamic diameter, and so on. Furthermore, dual-emission fluorescent AgNCs was used to sense ROS in tumor with different degrees of differentiation. Finally, the relationship between specific types of ROS and tumor cell invasion was explored by cell migration ability and the expression of cell adhesion and EMT markers. Results This dual-emission fluorescent AgNCs possessed an excellent ability to sensitively and selectively distinguish highly reactive oxygen species (hROS, including O2•-and •OH) from moderate reactive oxygen species (the form of H2O2), and exhibited no fluoresence and green fluorescence, respectively. The emission of AgNCs is effective in detecting cellular and tissular ROS. When cultured with AgNCs, malignant tumor cells exhibit non-fluorescence, while the benign tumor emits green and reduced red light and the normal cells appear in weak green and bright red fluorescence. We further verified that not just H2O2 but specific species of ROS (O2•-and •OH) were involved in cell invasion and malignant transformation. Our study warrants further research on the role of ROS in physiological and pathophysiological processes. Conclusion Taken together, AgNCs would be a promising approach for sensing ROS, and offer an intelligent tool to detect different kinds of ROS in tumors. © The author(s).The prognosis of pancreatic cancer remains poor. Intraoperative fluorescence imaging of tumors could improve staging and surgical resection, thereby improving prognosis. However, imaging pancreatic cancer with macromolecular delivery systems, is often hampered by nonspecific organ accumulation. Methods We describe the rational development of hyaluronic acid (HA) conjugates that vary in molecular weight and are conjugated to near infrared fluorescent (NIRF) dyes that have differences in hydrophilicity, serum protein binding affinity, and clearance mechanism. We systematically investigated the roles of each of these properties on tumor accumulation, relative biodistribution, and the impact of intraoperative imaging of orthotopic, syngeneic pancreatic cancer. Results Each HA-NIRF conjugate displayed intrapancreatic tumor enhancement. Regardless of HA molecular weight, Cy7.5 conjugation directed biodistribution to the liver, spleen, and bowels. Conjugation of IRDye800 to 5 and 20 kDa HA resulted in low liver and spleen signal while enhancing the tumor up to 14-fold compared to healthy pancreas, while 100 kDa HA conjugated to IRDye800 resulting in liver and spleen accumulation. Conclusion These studies demonstrate that by tuning HA molecular weight and the physicochemical properties of the conjugated moiety, in this case a NIRF probe, peritoneal biodistribution can be substantially altered to achieve optimized delivery to tumors intraoperative abdominal imaging. © The author(s).Rationale Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. Methods Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. Results CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. Conclusions CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable. © The author(s).
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