This study aimed to investigate the role of protein disulfide isomerase A3 (PDIA3) in oral squamous cell carcinoma (OSCC) and evaluate its significance as a diagnostic and prognostic biomarker.
p21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases, which are associated with cytoskeletal organization, cellular morphogenesis, migration and survival. PAKs are overactive in a number of tumor tissues and have attracted attention as a potential target for cancer therapy. In the present study, PAK5 levels were analyzed in primary osteosarcoma (OS) samples (n=65) using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) methods. In the primary OS tissue, increased PAK5 expression (IHC score >2, n=37) was associated with significantly decreased overall survival (P=0.036) compared with decreased PAK5 expression (IHC score ≤2, n=28). PAK5 expression was identified to be significantly associated with metastasis (P=0.010). The lung is the most common metastasis site for OS. In addition, the level of PAK5 in lung metastasis tissue (n=13) was detected using RT-qPCR and IHC methods. PAK5 expression was increased in lung metastasis tissue compared with in primary OS samples. PAK5 was silenced using short hairpin RNA in OS cell lines. Wound healing, migration and nude mice model assay results consistently demonstrated that PAK5 knockdown was able to significantly inhibit OS migration. In PAK5-knockdown cells, the alteration in the expression of a number of metastasis-associated factors, including epithelial cadherin, vimentin, fibronectin and matrix metalloproteinase 2 (MMP2), was analyzed. Only MMP2 expression was decreased significantly (P<0.05). The expression level of MMP2 was analyzed in primary OS tissue and lung metastasis tissue using RT-qPCR and IHC methods. Expression of MMP2 was identified to be associated with expression of PAK5. The results of the present study suggest that PAK5 promotes OS cell migration and that PAK5 expression may be used to predict lung metastasis.
The targeted small-molecule drug AZD6244 is an allosteric, ATP-noncompetitive inhibitor of MEK1/2 that has shown activity against several malignant tumors. Here, we report that AZD6244 repressed cell growth and induced apoptosis and G1-phase arrest in the breast cancer cell lines MDA-MB-231 and HCC1937. Using microRNA (miRNA) arrays and quantitative RT-PCR, we found that miR-203 was up-regulated after AZD6244 treatment. In accordance with bioinformatics and luciferase activity analyses, CUL1 was found to be the direct target of miR-203. Furthermore, miR-203 inhibition and CUL1 overexpression reversed the cytotoxicity of AZD6244 on the MDA-MB-231 and HCC1937 cells. Collectively, our data indicate that miR-203 mediates the AZD6244-induced cytotoxicity of breast cancer cells and that the MEK/ERK/miR-203/CUL1 signaling pathway may participate in this process.
Luteolin is a falvonoid compound derived from Lonicera japonica Thunb. Numerous reports have demonstrated that luteolin has anticancer effects on many kinds of tumors. This study investigated the effects of luteolin on prostate cancer (PCa), assessing the PC3 and LNCaP cells. The cell viability and apoptosis were assessed by performing Cell Counting Kit-8 assay and Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Luteolin was found to inhibit androgen-sensitive and androgen-independent PCa cell lines' growth and induced apoptosis. To uncover the exact mechanisms and molecular targets, microRNA (miR) array analysis was performed. miR-301 was found to be markedly downregulated. Then, the expression of miR-301 was retrospectively analyzed in the primary PCa tissues by quantitative reverse transcription polymerase chain reaction and in situ hybridization methods. According to the quantitative reverse transcription polymerase chain reaction results of miR-301, the 54 PCa patients were divided into two groups: high and low miR-301 groups. The division indicator is a relative expression ≥5. Compared to the low-expression group, high miR-301 expression was associated with a significantly shorter overall survival (P=0.029). The proapoptotic gene, DEDD2, was predicted to be the direct target of miR-301. It was clarified in accordance with bioinformatics and luciferase activity analyses. The overexpression of miR-301 by plasmid decreased the luteolin effect. Taken together, these results suggest that luteolin inhibits PCa cell proliferation through miR-301, the poor predictive factor of PCa.
11031 Background: Prognosis for patients with relapsed/metastatic osteosarcoma is dismal and the optimal treatment strategy remains to be refined. Sorafenib and sorafenib plus everolimus are the only two second-line targeted therapies recommend by FDA. The median progression-free survival (PFS) was 4–5 months. In this study, the efficacy and safety of apatinib, another oral tyrosine kinase inhibitor targeting VEGFR-2, were evaluated in patients (pts) with inoperable high-grade osteosarcoma progressing after standard multidisciplinary treatment. Methods: This retrospective study reviewed the medical records of 26 pts with metastatic osteosarcoma who received apatinib at a dose of 500 mg qd or 250 mg bid after failure of standard treatment including doxorubicin, cisplatin, ifosfamide and high-dose methotrexate from Jul 2015 to Nov 2016. Results: Among all pts, 25 (96.2%) had pulmonary metastases and 4 (15.4%) had metastases in the bone (Table). Eleven pts achieved partial response, 10 stable disease and 5 progressive disease, yielding an objective response rate of 42.3% and a clinical benefit rate of 80.8%. Followed up to Dec 31 2016, the median PFS was 8 months (95%CI, 3.2–12.8 months), and the median overall survival (OS) was not reached. The 12-month PFS and OS rates were 22.5% (95%CI, 1.6%–58.1%) and 68.7% (95%CI, 37.5%–86.5%), respectively. Noteworthy, the 12-month PFS rate for patients treated with apatinib in the second-line setting was 51.3% (95%CI, 9.1%–83.1%). The most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (HFSR) (84.6%), hypertension (46.2%), and diarrhea (23.1%). Severe AEs included grade 3 HFSR (7.7%) and hypertension (3.8%). No unexpected AE was found. Conclusions: Apatinib was well tolerated and demonstrated activity as a second- or later-line treatment in patients with metastatic osteosarcoma, which deserves further investigations. [Table: see text]
Immunotherapy has achieved revolutionary success in clinics, but it remains challenging for treating hepatocellular carcinoma (HCC) characterized by high vascularization. Here, it is reported that metal-organic framework-801 (MOF-801) can be employed as a stimulator of interferon genes (STING) through Toll-like receptor 4 (TLR4) not just as a drug delivery carrier. Notably, cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) and 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) STING agonist with vascular disrupting function coordinates with MOF-801 to self-assemble into a nanoparticle (MOF-CpG-DMXAA) that effectively delivers CpG ODNs and DMXAA to cells for synergistically improving the tumor microenvironment by reprogramming tumor-associated macrophages (TAMs), promoting dendritic cells (DCs) maturation, as well as destroying tumor blood vessels. In HCC-bearing mouse models, it is demonstrated that MOF-CpG-DMXAA triggers systemic immune activation and stimulates robust tumoricidal immunity, resulting in a superior immunotherapeutic efficiency in orthotopic and recurrent HCC.
Abstract The actin‐binding protein profilin1 (PFN1) plays a central role in actin dynamics, which is essential for cytotoxic T lymphocyte (CTL) functions. The functional role of PFN1 in CTLs, however still remains elusive. Here, we identify PFN1 as the only member of the profilin family expressed in primary human CD8 + T cells. Using in vitro assays, we find that PFN1 is a negative regulator of CTL‐mediated elimination of target cells. Furthermore, PFN1 is involved in activation‐induced lytic granule (LG) release, CTL migration and modulation of actin structures at the immunological synapse (IS). During CTL migration, PFN1 modulates the velocity, protrusion formation patterns and protrusion sustainability. In contrast, PFN1 does not significantly affect migration persistence and the rates of protrusion emergence and retraction. Under in vitro conditions mimicking a tumor microenvironment, we show that PFN1 downregulation promotes CTL invasion into a 3D matrix, without affecting the viability of CTLs in a hydrogen peroxide‐enriched microenvironment. Highlighting its potential relevance in cancer, we find that in pancreatic cancer patients, PFN1 expression is substantially decreased in peripheral CD8 + T cells. Taken together, we conclude that PFN1 is a negative regulator for CTL‐mediated cytotoxicity and may have an impact on CTL functionality in a tumor‐related context.
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