Herceptin-conjugated liposomes loaded with lipocalin-2 siRNA for the treatment of Inflammatory Breast Cancer
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PROVIDER: PRJNA1163003 | ENA |
REPOSITORIES: ENA
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Project description:Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer (BC) that regularly affects women younger than 40 years and accounts for 1 to 5% of all types of BC. There is not an optimal treatment for women with IBC. Approximately 40% of IBC patients are HER2+, which can be treated with the monoclonal antibody-based therapy, Herceptin (trastuzumab). However, more than 25% of patients become resistant to trastuzumab-based therapy in early stages and about 75% in late stages patients and effective second line targeted therapies are currently unavailable for IBC patients. Lipocalin-2 (LCN2) is a is a secreted protein involved in iron homeostasis, immune responses, transportation of siderophores for degradation, and epithelial cell differentiation. LCN-2 is highly abundant in certain subtypes of aggressive cancers including IBC. Reports have shown that LCN-2 is a potential target therapy for IBC patients. Here, we developed a double targeted therapy of liposomal-Herceptin formulation loaded with LCN2-targeted small interference RNA (siRNA). Trastuzumab DSPE-PEG(2000)-maleimide conjugates were synthesized for liposomal formulation, resulting in sizes of 18.3 nm and 73.7 nm for free DSPE-PEG(2000)-trastuzumab and trastuzumab-liposome, respectively. This formulation was efficiently internalized into HER2+ IBC cells, and reduced cell proliferation and tumor emboli formation in IBC cells. To further understand the molecular mechanism downstream LCN-2, we performed RNA-sequencing (RNA-seq), and we identified 139 differentially expressed genes upon siRNA-mediated LCN-2 knockdown in IBC cells. Ingenuity Pathway Analysis grouped the RNA-seq data into 25 canonical pathways altered downstream LCN-2. Together, this information suggests that LCN2-target siRNA within Herceptin-conjugated liposomes is a potential therapeutic strategy against IBC.
2025-07-30 | GSE277628 | GEO
Project description:In the present study, we prepared a novel theranostic agent loaded with LINC00511-siRNA, which not only can serve as the siRNA delivery platform but also as the UCA for contrast enhanced ultrasound (CEUS). Combined with low-frequency ultrasound exposure, the novel theranostic agent achieves the controlled release of LINC00511-siRNA and facilitates the transfection of LINC00511-siRNA. Furthermore, in order to investigate how LINC00511 affects drug resistance of TNBC, we conducted the RNA-Seq to gain new insights into the mechanisms of drug sensitivity.
2020-09-03 | GSE140729 | GEO
Project description:While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. Applying RNA sequencing analysis in renal CAKI1 tumor cells to explore highly upregulated molecular signatures in response to hLcn-2, we identified a cluster of genes (SLC7A11, GCLM, GLS), which are implicated in regulating ferroptosis. Indeed, hLcn-2-stimulated cells are protected from erastin-induced ferroptosis. We also noticed a rapid increase in reactive oxygen species (ROS) with subsequent activation of the antioxidant Nrf2 pathway. However, knocking down Nrf2 by siRNA was not sufficient to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. In contrast, preventing oxidative stress through N-acetyl-L-cysteine (NAC) supple-mentation was still able to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. Besides an oxidative stress response, we noticed activation of the integrated stress response (ISR), shown by enhanced phosphorylation of eIF-2α and induction of ATF4 after hLcn-2 addition. ATF4 knockdown as well as inhibition of the ISR sensitized hLcn-2-treated renal tumor cells to ferroptosis, thus linking the ISR to pro-tumor characteristics of hLcn-2. Our study provides mechanistic details to better understand tumor pro-survival pathways initi-ated by iron-loaded Lcn-2.
2021-06-02 | GSE171939 | GEO
Project description:Lipocalin-2 promotes acute lung inflammation
2023-02-28 | GSE198406 | GEO
Project description:Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer
| PRJNA590703 | ENA
Project description:Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2-/- mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in WT mice injected with LPS, Lcn2-/- mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared to WT mice injected with LPS, Lcn2-/- mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, NOD-like receptor signaling, and Jak-STAT signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.
2016-10-20 | GSE88959 | GEO
Project description:Perotein corona is formed surrouding interface of nanopsrticles upon administered in biological fluids. The quality of protein corona is recognized as the crucial factor for in vivo fate of the administered nanoparticles. In this project, Cas9 ribnonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) capable of robust gene knockout of hepatic genes of interest after single intravenous injection were developed. Compared with short interfering RNA (siRNA)-loaded LNPs, RNP-loaded LNPs showed different morphology, biodistribution, and mechanism of hepatic acccumulation. Therefore, proteome analysis of the corona proteins on the RNP and siRNA-loaded LNPs were performed to elucidate the impact of payloads on nano-bio interactions.
2024-09-05 | PXD055572 | JPOST Repository
Project description:Lipocalin-2 deficiency attenuates acute lung inflammation
| PRJNA814910 | ENA
Project description:Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under pre-clinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernable impact on systemic energy homeostasis, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.
2021-02-02 | PXD022682 | Pride
Project description:Amino Acid Conjugated Surfaces and Controls 32 Hours Time Point Keywords: parallel sample
2004-01-28 | GSE999 | GEO