Ovarian cancer is the most lethal gynecological malignancy worldwide with high metastasis and poor prognosis rates. Cancer‐associated fibroblasts (CAFs), a heterogeneous population of cells that constitutes a major component of the tumor microenvironment, secrete extracellular vesicles (EVs) loading with proteins, lipids, and RNAs to promote tumorigenesis. However, the specific roles of CAF‐derived proteins contained in EVs in ovarian cancer remain poorly understood at present. Using the gene expression microarray analysis, we identified a list of dysregulated genes between the α‐SMA+CAF and FAP+CAF subpopulations, from which secretory leukocyte protease inhibitor (SLPI) was chosen for further validation. Quantitative PCR, western blot, immunohistochemistry, and enzyme‐linked immunosorbent assays were used to assess SLPI expression in ovarian cancer cells, tissues, CAFs, and EVs. Additionally, we evaluated the effects of exogenous SLPI on proliferation, migration, invasion, and adhesion of ovarian cancer cells in vitro. Our results showed SLPI protein was upregulated in CAFs, particularly in the FAPhighα‐SMAlowCAF subpopulation, and associated with increased tumor grade and decreased overall survival (OS). Importantly, CAF‐derived SLPI protein could be encapsulated in EVs for delivery to ovarian cancer cells, thus facilitating cell proliferation, migration, invasion, and adhesion via activating the PI3K/AKT and downstream signaling pathways. Moreover, high plasma expression of SLPI encapsulated in EVs was closely correlated with tumor stage in ovarian cancer patients. Our collective results highlight an oncogenic role of plasma EV‐encapsulated SLPI secreted by CAFs in tumor progression for the first time, supporting its potential utility as a prognostic biomarker of ovarian cancer.
Background Profilin-1 (PFN1) regulates the dynamic balance of actin and plays an important role in cell functions as a hub protein in signaling molecule interaction networks. Dysregulation of PFN1 is related to pathologic kidney diseases. Diabetic nephropathy (DN) was recently reported as an inflammatory disorder, however, the molecular mechanisms of PFN1 in DN remain unclear. Therefore, the present study was conducted to explore the molecular and bioinformatic characteristics of PFN1 in DN. Methods Bioinformatics analyses were performed on the chip of database in DN kidney tissues. A cellular model of DN was established in human renal tubular epithelial cells (HK-2) induced by high glucose. The PFN1 gene was overexpressed or knocked-down to investigate its function in DN. Flow cytometry was used to detect cell proliferation and apoptosis. PFN1 and proteins in the related signaling pathways were evaluated by Western blotting. Results The expression of PFN1 was significantly increased in DN kidney tissues ( P < 0.001) and was correlated with a high apoptosis-associated score (Pearson’s correlation = 0.664) and cellular senescence-associated score (Pearson’s correlation = 0.703). PFN1 protein was mainly located in cytoplasm. Overexpression of PFN1 promoted apoptosis and blocked the proliferation of HK-2 cells treated with high levels of glucose. Knockdown of PFN1 led to the opposite effects. Additionally, we found that PFN1 was correlated with the inactivation of the Hedgehog signaling pathway in HK-2 cells treated with high levels of glucose. Conclusion PFN1 might play an integral role in the regulation of cell proliferation and apoptosis during DN development by activating the Hedgehog signaling pathway. This study provided molecular and bioinformatic characterizations of PFN1, and contributed to the understanding of the molecular mechanisms leading to DN.
Ionizing radiation (IR) is an important treatment for nasopharyngeal carcinoma (NPC) that mainly kills tumor cells by producing large amounts of reactive oxygen species (ROS). Intracellular ROS levels affect the sensitivity of tumor cells to IR. Recently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-converting enzyme (ACE) have been found to affect the intracellular levels of ROS. Therefore, we performed a health informatics assessment of ACE in the TCGA database. We explored the effect of ACE in NPC cells. We found that either knockdown of ACE or inhibition of ACE by enalaprilat could decrease ROS levels in NPC cells. Furthermore, knockdown of ACE or inhibition of ACE by enalaprilat could reduce IR-induced ROS levels. ACE knockdown or inhibition reduced IR-induced DNA damage and apoptosis. ACE overexpression increased the level of ROS in NPC cells and further increased sensitivity to IR. These findings indicate that ACE influences the effect of IR by regulating the level of ROS in NPC cells.
<div>Abstract<p><b>Purpose:</b> Triple-negative breast cancer (TNBC) is a high risk form of this disease, even after surgery, due to the absence of targets for hormone treatment and anti–Her-2 therapy. Chemotherapy is the main therapeutic strategy for such patients with breast cancer, although the outcome is often unsatisfactory. Thus, the development of combination adjuvant therapies is essential for improved prognosis in patients with TNBC. In this study, we investigated the efficacy of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with post-mastectomy TNBC.</p><p><b>Experimental Design:</b> From 2008 to 2012, 90 patients with post-mastectomy TNBC were included in this retrospective study: 45 cases received chemotherapy alone or with sequential radiotherapy; a further 45 cases received chemotherapy with/without radiotherapy and sequential CIK infusion.</p><p><b>Results:</b> Survival analysis showed significantly higher disease-free survival (DFS) and overall survival (OS) rates in the CIK treatment group compared with the control group (<i>P</i> = 0.0382, <i>P</i> = 0.0046, respectively; log-rank test). Multivariate survival analysis showed that CIK adjuvant treatment was an independent prognostic factor for OS of patients with TNBC. In subgroup analyses, CIK adjuvant treatment significantly increased the DFS rate of patients with pathologic grade 3, and significantly increased the OS rate of patients in N1, N2, N3, IIB, III TNM (tumor–node–metastasis) stages, and with pathologic grade 3.</p><p><b>Conclusions:</b> These data indicate that adjuvant CIK treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with TNBC, particularly those with lymph node metastasis, advanced TNM stage, and poor pathologic grade. <i>Clin Cancer Res; 20(11); 3003–11. ©2014 AACR</i>.</p></div>
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