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Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.

Background/Aims: Multidrug resistance (MDR) is the most common cause of chemotherapy failure. Upregulation of P-glycoprotein (P-gp) is one of the main mechanisms underlying MDR. Methods: In this study, we developed a targeted drug and small interfering (si)RNA co-delivery system based on specific aptamer-conjugated grapefruit-derived nanovectors (GNVs) that we tested in MDR LoVo colon cancer cells. The internalization of nanovectors in cancer cells was tested by fluorescence microscopy and flow cytometry. The anti-cancer activity in vitro was determined by colony formation and cell apoptosis assays. The biodistribution of nanovectors was analyzed by live imaging and the anti-cancer activity in vivo was observed. Results: GNVs loaded with aptamer increased doxorubicin (Dox) accumulation in MDR LoVo cells, an effect that was abolished by pretreatment with DNase. The LA1 aptamer effectively promoted nanovector internalization into cells at 4°C and increased the targeted delivery of Dox to tumors. Constructs harboring Dox, LA1, and P-gp siRNA more effectively inhibited proliferation and enhanced apoptosis in cultured MDR LoVo cells while exhibiting more potent anti-tumor activity in vivo than free Dox or GNVs loaded with Dox alone or in conjunction with LA1, an effect that was associated with downregulation of P-gp expression. Conclusion: This GNV-based system may be an effective strategy for overcoming MDR in clinical settings.

Background Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFR apt ) modification. Results Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFR apt -miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFR apt , was developed. In vitro analysis demonstrated that 4WJ-EGFR apt -miR-375-PTX possesses strong thermal and pH stabilities. EGFR apt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFR apt -miR-375-PTX was selectively distributed in tumor sites via EGFR apt -mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. Conclusion This strategy may provide a practical approach for targeted therapy of ESCC. Graphical Abstract

Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal cancer characterized by high mortality and an unfavorable prognosis. While combination therapies involving surgery, chemotherapy, and radiation therapy are advancing, targeted therapy for ESCC remains underdeveloped. As a result, the overall five‐year survival rate for ESCC is still below 20%. Herein, ESCC‐specific DNA aptamers and an innovative aptamer‐modified nano‐system is introduced for targeted drug and gene delivery to effectively inhibit ESCC. The EA1 ssDNA aptamer, which binds robustly to ESCC cells with high specificity and affinity, is identified using cell‐based systematic evolution of ligands by exponential enrichment (cell‐SELEX). An EA1‐modified nano‐system is developed using a natural egg yolk lipid nanovector (EA1‐EYLNs‐PTX/siEFNA1) that concurrently loads paclitaxel (PTX) and a small interfering RNA of Ephrin A1 (EFNA1). This combination counters ESCC's proliferation, migration, invasion, and lung metastasis. Notably, EFNA1 is overexpressed in ESCC tumors with lung metastasis and has an inverse correlation with ESCC patient prognosis. The EA1‐EYLNs‐PTX/siEFNA1 nano‐system offers effective drug delivery and tumor targeting, resulting in significantly improved therapeutic efficacy against ESCC tumors. These insights suggest that aptamer‐modified nano‐systems can deliver drugs and genes with superior tumor‐targeting, potentially revolutionizing targeted therapy in ESCC. Ephrin A1 (EFNA1) is upregulated in esophageal squamous cell carcinoma (ESCC) with pulmonary metastasis and correlates with poor prognosis, meanwhile EA1 aptamer exhibits robust binding to ESCC cells with remarkable specificity. Consequently, they engineered an EA1‐modified nano‐system utilizing a natural egg yolk lipid nanovector (EA1‐EYLNs‐paclitaxel/siEFNA1) that offers enhanced drug/gene delivery and tumor targeting capabilities, exhibiting excellent ESCC cancer suppression efficiency.

Mps1/TTK plays an important role in development of many tumors. The purpose of the present study was designed to investigate the role of TTK in colon cancer. We analyzed TTK and colon cancer in the GEO database, colon cancer tissues and normal tissues were collected to verify the results by immunohistochemistry. We detected the TTK expression in the colon cancer cell lines, and overexpressed or silenced TTK expression in colon cancer cell lines. GEO database showed that the expression of TTK was higher in the colon cancer tissues than normal tissues, higher level of TTK shows unfavourable prognosis in colon patients. Furthermore, high differentiation of colon shows the lower expression of TTK. The higher expression of TTK links with the high microsatellite status. However, the expression of TTK has no significant difference among the different stages of colon cancer patients, and has no significant relationship with recurrence or relapse. Here, we also report that the differential expression of TTK in colon cancer cells alters the intrinsic negative regulation of cell proliferation and differentiation, resulting in the difference of proliferation and differentiation capacity. TTK could activate the PKCα/ERK1/2 to influence the proliferation and inactivate the PI3K/AKT pathway to inhibition the expression of MUC2 and TFF3 that related to the differentiation of colon cells. In conclusions, TTK promote the colon cancer cell proliferation via activation of PKCα/ERK1/2 and inhibit the differentiation via inactivation of PI3K/Akt pathway. TTK inhibition may be the potential therapeutic pathway for the treatment of colon cancer.

Chemotherapy is the primary treatment for most cancers apart from surgery. However, the use of chemotherapeutic drugs is limited by side effects and restricted accumulation in tumors because of unique tumor microenvironments. Macrophages have excellent drug delivery potential owing to their chemotaxis and can home in on tumors. We developed an effective drug-delivery system for doxorubicin using macrophages. Doxorubicin-loaded egg yolk lipid-derived nanovectors (EYLNs-Dox) were prepared, EYLNs-Dox-loaded macrophages (Mac/EYLNs-Dox) were developed and their tumor penetration and anti-cancer activity against 4T1 cells were analyzed. The biodistribution and anti-4T1 breast cancer activities were determined using 4T1 subcutaneous and lung metastasis models. EYLNs-Dox was successfully internalized into macrophages without affecting their viability and was less toxic than Dox. Mac/EYLNs-Dox penetrated the 4T1 tumor spheroids more efficiently and was more effective in inhibiting tumors in vitro. Macrophages significantly enhanced the distribution of EYLNs vectors in both inflammatory and tumor sites, playing a more effective role in the inhibition of tumors. EYLNs-Dox can be effectively delivered using macrophages and Mac/EYLNs-Dox might be a promising targeted delivery system for breast cancer.

Lv Y, Jun Y, Tang Z, et al. Int J Nanomedicine.2020;15:10075-10084. The authors have advised due to an error at the time offigure assembly, Figure 5C on page 10082 is incorrect.The correct Figure 5 is shown below. The authors apologize for this error and advise it does notaffect the results of the paper. Read the original article

Background Maternally expressed 3 (MEG3) plays an important role in cervical cancer development, but its exact role remains unclear. Here, we explored the specific regulatory mechanism of MEG3 and its downstream proteins in cervical cancer cells. Methods The effect of MEG3 on tumor formation ability of cervical cancer cells was determined in nude mice. The direct binding of MEG3 to phosphorylated signal transducer and activator of transcription 3 (P-STAT3) was detected by RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assays. Cycloheximide (CHX)-chase and ubiquitination assays were performed to determine the regulatory effect of MEG3 on P-STAT3 ubiquitination. Clone formation assay and flow cytometry were used to evaluate the effect of the MEG3-STAT3 regulatory axis on cell proliferation and apoptosis. Results In vivo tumor formation experiments showed that MEG3 inhibited the tumor formation ability of cervical cancer cells. RNA pull-down and RIP assays demonstrated that MEG3 bound directly to P-STAT3 protein. CHX-chase and ubiquitination assay results showed that MEG3 promoted P-STAT3 degradation via ubiquitination. Clone formation assay and flow cytometry analysis results revealed that the inhibitory effect of MEG3 on P-STAT3 promoted apoptosis and inhibited proliferation of cervical cancer cells. Conclusion MEG3 binds to P-STAT3 in cervical cancer cells, resulting in P-STAT3 ubiquitination and degradation and apoptosis and inhibition of proliferation of tumor cells. The in-depth elaboration of the MEG3-STAT3 regulatory axis in cervical cancer may clarify the mechanism of action of MEG3 and provide new ideas for cervical cancer treatment.

Recent studies have suggested that lincRNA-ROR is involved in the tumorigenesis of different types of cancers. However, the role of lincRNA-ROR in retinoblastoma has not been determined. We investigated lincRNA-ROR levels in 58 retinoblastoma and adjacent non-tumor tissues by quantitative reverse transcription PCR. Recurrence-free survival was analyzed using Cox regression analyses. Cell migration and invasion abilities were detected by wound-healing, Transwell invasion, and bioluminescence imaging assays. Western blotting was performed to detect epithelial–mesenchymal transition markers. Interactions between lincRNA-ROR, miR-32-5p, and Notch1 were confirmed by Luciferase, RNA pull-down, and RIP assays. Histone acetylation was detected by chromatin immunoprecipitation assays. We showed that lincRNA-ROR was significantly upregulated in retinoblastoma tissues, and overexpression of lincRNA-ROR was significantly correlated with optic nerve invasion, nodal or distant metastasis, and recurrence. We also showed that lincRNA-ROR is a critical promoter of retinoblastoma cell metastasis, both in vivo and in vitro. Further, we demonstrated that lincRNA-ROR activates the Notch signaling pathway by acting as a sponge of miR-32-5p. Upregulation of lincRNA-ROR was attributed to the CBP-mediated H3K27 acetylation at the promoter region. Our results reveal a potential competing endogenous RNA regulatory pathway, in which lincRNA-ROR modulates the epithelial–mesenchymal transition program by competitively binding to endogenous miR-32-5p and regulating Notch signaling pathway activity in retinoblastoma cells, which may provide new insights into novel molecular therapeutic targets for retinoblastoma.

Background Maternally Expressed Gene 3 ( MEG3 ) is expressed at low levels in placental villi during preeclampsia; however, its roles in unexplained recurrent spontaneous abortion (URSA) remain unclear. In this study, we aimed to explore the relationship between MEG3 and URSA. Methods The differentially expressed lncRNAs ( MEG3 ) and its downstream genes ( RASA1 ) were identified using bioinformatics analysis of Genomic Spatial Event (GSE) database. The expression levels of MEG3 in embryonic villis (with gestational ages of 49–63 days) and primary trophoblasts were determined using quantitative RT-PCR assay. A mouse model of Embryo implantation, Cell Counting Kit-8 (CCK-8), flow cytometry, and Transwell migration assays were performed to determine the implantation, proliferative, apoptotic, and invasive capacities of trophoblast. The level of phosphorylated core proteins in the RAS-MAPK pathway were analyzed using Western blot assay. The mechanisms of MEG3 in the regulation of RASA1 were studied by RNA pulldown, RNA immunoprecipitation (RIP), DNA pulldown, and chromatin immunoprecipitation (ChIP) assays. Results MEG3 had a low expression level in embryonic villis of 102 URSA patients compared with those of 102 normal pregnant women. MEG3 could promote proliferation and invasion, inhibit the apoptosis of primary trophoblast of URSA patients (PT-U cells), as well as promote embryo implantation of mouse. Besides, MEG3 also promoted the phosphorylation of rapidly accelerated fibrosarcoma (Raf), mitogen-activated protein kinase kinase (MEK), and extracellular-signal-regulated kinase (ERK) proteins. The results of RNA pull down and RIP assays showed that MEG3 bound with the enhancer of zeste homolog 2 (EZH2). The DNA pulldown assay revealed that MEG3 could bind to the promoter sequence of the RAS P21 Protein Activator 1 ( RASA1 ) gene. Further, the ChIP assay showed that MEG3 promoted the binding of EZH2 to the promoter region of the RASA1 gene. Conclusions The inactivation of MEG3 in embryonic villi association with URSA; MEG3 inhibited the expression of RASA1 by mediating the histone methylation of the promoter of RASA1 gene by EZH2, thereby activating the RAS-MAPK pathway and enhancing the proliferative and invasive capacities of trophoblasts.