Extracellular matrix (ECM) is crucial in various biological functions during tumor progression, including induction of anoikis resistance and cell adhesion‐mediated drug resistance (CAM‐DR). Fibronectin (FN) is a vital ECM component with direct regulatory effects on ECM‐mediated anoikis resistance and CAM‐DR, making it an attractive and innovative therapeutic target for depriving ECM in tumor tissue. Herein, an ECM deprivation system (EDS) is developed based on FN targeting self‐assembly peptide for constructing nanofibers in the ECM of renal cell carcinoma (RCC), which contributes to: i) targeting and recognizing FN to form nanofibers for long‐term retention in ECM, ii) reversing anoikis resistance via arresting the FN signaling pathway, and iii) serving as a drug‐loading platform for sensitizing chemotherapy by ameliorating CAM‐DR. The results reveal that EDS significantly reverses anoikis resistance of RCC cells by inhibiting the phosphorylation of FAK, a positive regulator of the FN signaling pathway. Meanwhile, EDS serves as a chemotherapy‐sensitizer of cancer, exerting significant synergistic effects with doxorubicin (DOX). In vivo validation experiments show that EDS effectively suppresses metastasis and tumor growth with chemotherapy resistance. Collectively, the innovative EDS notably inhibits the tumor‐promoting effect of ECM and may provide a novel approach for suppressing ECM and enhancing chemo‐drug sensitivity.
Tumor vasculature and cancer stem cells (CSCs) are two major hazards that accelerate this process. [2,3] Metastatic renal cancer is highly vascularized [4] and the abundant presence of CSCs Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual-inhibition system (TDS) based on a self-assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand-receptor interaction-induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human-derived CSCs, TDS inhibits stemness by reducing endogenic miR-19b and its transportation via CSCs-derived exosomes, which increases PTEN expression and consequently suppresses CSCs-mediated metastasis. In patient-derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0-fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer.
Frizzled class receptor 1 (FZD1), a receptor for Wnt signaling pathway . Overexpression of FZD1 has been detected in many cancer tissues and cells resulting in tumor development and drug resistance. However, its expression status and prognostic merit in renal cancer still remains unclear. We screened the FZD1 mRNA in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) from TCGA database and Oncomine database. We then detected FZD1 mRNA expression in sunitinib-resistant cells and the corresponding parental cells by qRT-PCR. FZD1 level was significantly upregulated in renal cancer tissues, renal cancer cell lines and their corresponding sunitinib-resistant cells. FZD1 level was also associated with the clinicopathological characteristics of ccRCC patients that could discriminate metastasis, pathological stage, recurrence and prognosis in ccRCC patients. The Kaplan-Meier survival curve and the log-rank test revealed FZD1 was higher in lower clinical stage and grade that correlated with better overall survival (OS) and disease-free survival (DFS) in total and subgroups of ccRCC patients. Both univariate and multivariate cox regression analysis indicated that high FZD1 level was an independent predictor of good prognosis for OS (HR 0.569, P=0.001) and DFS (HR 0.559, P=0.036) in ccRCC patients. Using cBioportal program, less than 1% mutation in the patients with renal cancer was observed, the alterations in FZD1 were correlated with better OS (P=0.0404) in ccRCC patients. Finally, the result of KEGG pathway analysis predicted seven potential pathways that FZD1 and its related genes got involved in ccRCC, including Hippo signaling pathway. This indicated potential therapeutic targets of ccRCC. In conclusion, our results suggested that expression status of FZD1 had a diagnostic value and prognostic value in ccRCC patients, it also may serve as a potential drug target to relieve sunitinib resistance in renal cancer patients.
Bladder cancer (BC) is the most common malignancy involving the urinary system, and is characterized by a high recurrence rate. It is important to identify potential lncRNA signatures capable of predicting tumour recurrence risk and assessing recurrence prognosis in BC patients. We extracted data from The Cancer Genome Atlas and identified 381 differentially expressed lncRNAs, 855 mRNAs and 70 miRNAs between non-recurrent and recurrent BC tissues. Subsequently, a competing endogenous RNA (ceRNA) network composed of 29 lncRNAs, 13 miRNAs and 4 mRNAs was established. We used univariate and multivariate Cox regression to analyse the relationship between the 29 lncRNAs and recurrence-free survival (RFS) in BC patients. Six lncRNAs had significant prognostic values, and their cumulative risk score indicated that this 6-lncRNA signature independently predicted RFS in BC patients. We applied a receiver operating characteristic (ROC) analysis to assess the efficiency of our prognostic models. High-risk patients exhibited a poorer prognosis than low-risk patients did. Additionally, the 6-lncRNA signature showed a significant correlation with BC clinicopathological characteristics, which indicates that it could be used for effective risk stratification. The current study provides novel insights into the lncRNA-related ceRNA network and this 6-lncRNA signature may be an independent prognostic factor in predicting the recurrence of BC patients.
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