BEX3 contributes to cisplatin chemoresistance in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) can develop cisplatin-resistant phenotype. Research has revealed that enriched in cancer stem cell population is involved in developing cisplatin-resistant phenotype. CD271 is a candidate stem cell maker in head and neck cancers. The CD receptor does not possess any enzymatic property. Signal transduction function of CD271 is mediated by the cellular receptor-associated protein. Our data showed that Brain-expressed X-linked 3 (BEX3), a CD271 receptor-associated protein, was overexpressed in NPC. BEX3 overexpression was a unique event in cancer developed in the head and neck regions, especially NPC. BEX3 expression was inducible by cisplatin in NPC. In cisplatin-resistant NPC xenograft, treatment with nontoxic level of cisplatin led to a remarkable increase in BEX3 level. High BEX3 expression was accompanied with high octamer-binding transcription factor 4 (OCT4) expression in cisplatin-resistant NPC. To confirm the inducing role of BEX3 on OCT4 expression, we knockdown BEX3 using siRNA and compared the expression of OCT4 with mock transfectants. Suppressing BEX3 transcripts led to a significant reduction in OCT4. In addition, targeting BEX3 using shRNA could increase the sensitivity of NPC cells to cisplatin. In summary, our results indicated a unique functional role of BEX3 in mediating the sensitivity of NPC cells to cisplatin. Targeting or blocking BEX3 activity might be useful in reversing the cisplatin-resistant phenotype in NPC.

MicroRNA-138-5p controls sensitivity of nasopharyngeal carcinoma to radiation by targeting EIF4EBP1.

Radiation therapy is the standard treatment for primary nasopharyngeal carcinoma (NPC). MicroRNA regulates cancer responsiveness to radiation therapy by controlling the genes involved in radiation responses. Recent studies suggested that downregulation of microRNA-138-5p was clinically significant in NPC. Here, we evaluated the effect of miR-138-5p on radiosensitivity of NPC cells and explored the underlying mechanisms by identifying its target gene that impacted sensitivity to radiation. Our results revealed that overexpression of miR-138-5p reduced the ability to form colonies, inhibited proliferation, and enhanced radiation-induced DNA damage and autophagy in NPC cells upon radiation treatment. By integrating predicted targets with the transcripts downregulated by miR-138-5p, EIF4EBP1 was identified to be a target gene of miR-138-5p. Results from luciferase reporter assay demonstrated that miR-138-5p downregulated the expression of EIF4EBP1 by binding to the 3'-UTR. Silence of EIF4EBP1 enhanced radiosensitivity of NPC cells as evidenced by reduced ability to form colonies after radiation exposure. In summary, our results indicated that miR-138-5p enhanced radiosensitivity of NPC cells by targeting EIF4EBP1. Further studies are warranted to investigate the potential use of miR-138-5p in the clinical management and treatment prediction of NPC patients.

The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis.

BACKGROUND: Programmed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors. METHODS: A systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests. RESULTS: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87-9.66) and digestive system cancer (OR 2.87, 95% CI 1.84-4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38-4.98), breast (HR: 1.86, 95% CI 1.36-2.54), digestive system (HR: 2.12, 95% CI 1.75-2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06-9.41). CONCLUSIONS: The current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.

MicroRNA 744-3p promotes MMP-9-mediated metastasis by simultaneously suppressing PDCD4 and PTEN in laryngeal squamous cell carcinoma.

MicroRNA controls cancer invasion by governing the expression of gene regulating migration and invasion. Here, we reported a novel regulatory pathway controlled by miR-744-3p, which enhanced expression of matrix metallopeptidase 9 (MMP-9) in laryngeal squamous cell carcinoma (LSCC). We profiled the differential micoRNA expression pattern in LSCC cell lines and normal epithelial cultures derived from the head and neck mucosa using microRNA microarray. MiR-7-1-3p, miR-196a/b and miR-744-3p were expressed differentially in the LSCC cell lines. Subsequent validation using real-time PCR revealed that high miR-744-3p level was positively correlated with regional lymph node metastasis of LSCC. Real-time cellular kinetic analysis showed that suppressing miR-744-3p could inhibit migration and invasion of LSCC cell lines and reduce the number of lung metastatic nodules in nude mice modules. In silico analysis revealed that miR-744-3p targeted 2 distinct signaling cascades which eventually upregulated MMP-9 expression in LSCC. First, miR-744-3p could suppress programmed cell death 4 (PDCD4), a direct suppressor of NF-κB (p65). PDCD4 could also prevent AKT activation and suppress MMP-9 expression. Further, suppressing miR-744-3p expression could restore phosphatase and tensin homolog (PTEN) expression. PTEN could inhibit AKT activation and inhibit MMP-9 expression in LSCC cells. The results revealed that suppressing miR-744-3p was effective to inhibit LSCC metastasis by inactivating AKT/mTOR and NF-κB (p65) signaling cascade. Targeting miR-744-3p could be a valuable therapeutic intervention to suppress the aggressiveness of LSCC.

Decreased brain-expressed X-linked 4 (BEX4) expression promotes growth of oral squamous cell carcinoma.

BACKGROUND: Brain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown. METHODS: Expression level of BEX family members (BEX1-5) in OSCC tissues and the paired normal epithelial were examined. Functions of epigenetic changes (DNA methylation and histone modifications) on BEX4 suppression in OSCC were examined by zebularine and trichostatin A (TSA) treatment on OSCC cell lines. Lentivector containing full-length BEX4 was used to generate OSCC cell lines with stable BEX4 expression. Effects of BEX4 expression on OSCC proliferation were monitored with xCELLigence RTCA real-time cell analyzer. BEX4-overexpressing CAL27 was implanted into nude mice to evaluate the effects on tumor growth in vivo. The signaling pathways regulated by BEX4 in OSCC was explored using human whole-transcript expression microarray. RESULTS: Among the 5 BEX family members, BEX1 and BEX4 showed significant down-regulation in OSCC (P < 0.001). BEX3, in comparison, was overexpressed in the primary tumor. BEX4 expression in OSCC cell lines was re-activated after zebularine and TSA treatment. High BEX4 expression could suppress proliferation of OSCC in vitro. Subcutaneous tumor volume of BEX4-overexpressing CAL27 was remarkably reduced in nude mice. Microarray experiment showed that S100A family members (S100A7, S100A7A, S100A8, S100A9 & S100A12) might be the downstream targets of BEX4 in OSCC. CONCLUSIONS: BEX4 functions as tumor suppressor by inhibiting proliferation and growth of oral cancer. Decreased BEX4 contributes to the increased proliferative propensity of OSCC.

The Efficacy of Triamcinolone Acetonide in Keloid Treatment: A Systematic Review and Meta-analysis.

Keloid is a cutaneous dermal outgrowth resulting from uncontrolled deposition of collagen and glycosaminoglycan around the wound. The uncontrolled and persistent growth of keloids scar will result in cosmetic disfigurement, functional impairment, and affect the quality of life. Triamcinolone acetonide (TAC) is traditionally employed in treating keloid scars. In this study, we aim to evaluate the effectiveness of TAC and compare it with other common therapy employed in keloid treatment. Only randomized controlled trial (RCT) and controlled trial were included. Inverse variance risk ratio, weighted mean difference, and corresponding 95% confidence intervals were calculated to evaluate the effect of intervention. Meta-analysis indicated that TAC treatment significantly reduced the size of keloid compared to untreated control. Reduction in size was statistically different in favor of TAC compared to silicone gel sheet. Significant difference in favor of TAC was observed compared with verapamil in term of vascularity and scar pliability. TAC treatment was more effective in reducing scar thickness in comparison with cryotherapy. However, the current meta-analysis has several limitations. Only a limited number of trials with the same comparison are available. Most trials recruited a small number of patients and used inconsistent outcome assessment. Most trials did not provide detail information on allocation concealment and blinding. Therefore, further evaluation in multi-center RCTs with consistent comparisons and outcome measurements are warrant to reach a consensus on the selection between TAC and different treatment modalities.

mTOR Pathway and mTOR Inhibitors in Head and Neck Cancer.

Head and neck cancer is the sixth most common type of Cancer worldwide. Since conventional treatment regimens are nonselective and are associated with systemic toxicities, intense investigations focus on molecular targeted therapy with high selectivity and low adverse effects. mTOR signaling pathway has been found to be activated in head and neck cancer, making it attractive for targeted therapy. In addition, expression levels of mTOR and downstream targets eIF4E, 4EBP1, S6K1, and S6 are potential diagnostic and prognostic biomarkers for head and neck cancer. mTOR inhibitors, such as rapamycin and its derivatives temsirolimus and everolimus, exhibit inhibitory effects on head and neck cancer in both in vitro cell line model and in vivo xenograft model. A large number of clinical trials have been initiated to evaluate the therapeutic effects of mTOR inhibitors on patients with head and neck cancer. mTOR inhibitor has potential as a single therapeutic agent or in combination with radiation, chemotherapeutic agents, or other targeted therapeutic agents to obtain synergistic repression on head and neck cancer.