MYO5A overexpression promotes invasion and correlates with low lymphocyte infiltration in head and neck squamous carcinoma.

Head and neck squamous carcinoma (HNSC) poses a significant public health challenge due to its substantial morbidity. Nevertheless, despite advances in current treatments, the prognosis for HNSC remains unsatisfactory. To address this, single-cell RNA sequencing (RNA-seq) and bulk RNA-seq data combined with in vitro studies were conducted to examine the role of MYO5A (Myosin VA) in HNSC. Our investigation revealed an overexpression of MYO5A in HNSC that promotes HNSC migration in vitro. Remarkably, knockdown of MYO5A suppressed vimentin expression. Furthermore, analyzing the TCGA database evidenced that MYO5A is a risk factor for human papillomavirus positive (HPV+) HNSC (HR = 0.81, P < 0.001). In high MYO5A expression HNSC, there was a low count of tumor infiltrating lymphocytes (TIL), including activated CD4+ T cells, CD8+ T cells, and B cells. Of note, CD4+ T cells and B cells were positively associated with improved HPV+ HNSC outcomes. Correlation analysis demonstrated a decreased level of immunostimulators in high MYO5A-expressing HNSC. Collectively, these findings suggest that MYO5A may promote HNSC migration through vimentin and involve itself in the process of immune infiltration in HNSC, advancing the understanding of the mechanisms and treatment of HNSC.

Long non-coding RNA AGAP2-AS1 promotes proliferation and metastasis in papillary thyroid cancer by miR-628-5p/KLF12 axis.

Long non-coding RNA (lncRNA) AGAP2-AS1 acts as an oncogene in several types of cancers. However, the role and mechanism of AGAP2-AS1 in papillary thyroid carcinoma (PTC) remain unclear. Thus, in this study, we aimed to explore the role of AGAP2-AS1 in PTC. Our results showed that AGAP2-AS1 was significantly upregulated in PTC tissues. Knockdown of AGAP2-AS1 inhibited the proliferation, migration and invasion of PTC cells. In vivo experiment showed that AGAP2-AS1 knockdown inhibited the tumorigenesis of PTC. MiR-628-5p was found to act as a target miRNA of AGAP2-AS1 in PTC. The expression level of miR-628-5p in PTC tissues was negatively associated with that of AGAP2-AS1. Inhibition of miR-628-5p attenuated the effects of AGAP2-AS1 knockdown on PTC. Moreover, miR-628-5p directly bound to the 3'UTR of KLF12 and inhibited the expression of KLF12. Knockdown of KLF12 enhanced the inhibitory effects of miR-628-5p on PTC cell proliferation and metastasis. In conclusion, these findings indicated that AGAP2-AS1 exerted an oncogenic role in PTC progression and metastasis. The effects of AGAP2-AS1 might be mediated by the regulation of miR-628-5p/KLF12 axis.

Genetic polymorphisms in the PCNXL2 gene are risk factors for thyroid cancer in the Chinese population.

Background: Thyroid cancer is the most common endocrine malignancy and the fastest growing cancer worldwide. Thyroid cancer has the largest genetic component of all cancers. Previous genome-wide association studies indicated that genetic polymorphism in PCNXL2 is related to thyroid cancer susceptibility in European populations. This study aims to determine the influence of PCNXL2 polymorphisms on thyroid cancer risk in Chinese individuals. Methods: This case-control study identified four polymorphisms in PCNXL2 among 510 thyroid cancer cases and 509 healthy controls. The associations of PCNXL2 polymorphisms with thyroid cancer susceptibility were detected by calculating odds ratios. Multifactor dimensionality reduction was performed to detect the impact of SNP (single nucleotide polymorphism)-SNP interactions on the risk of thyroid cancer. Results: The study showed that rs10910660 in PCNXL2 was related to thyroid cancer susceptibility. Rs12129938 played a protective role in thyroid cancer susceptibility. Stratification analysis indicated that rs10910660 increased thyroid cancer risk at age >45 years. Rs12129938 enhanced susceptibility to thyroid cancer at age >45 years, while this SNP decreased thyroid cancer risk at age ≤45 years. Rs4649295 was associated with lower susceptibility to thyroid cancer at age ≤45 years. An association was observed between rs6424270 and rs12129938 with decreased susceptibility to thyroid cancer in women. Rs10910660 was related to thyroid cancer risk in men. The combination of rs6424270, rs10910660, rs12129938 and rs4649295 was the best model to predict thyroid cancer. Conclusion: This study suggests that PCNXL2 polymorphisms are risk factors for thyroid cancer in the Chinese population.

Associations between expression levels of nine core nucleotide excision repair genes in lymphocytes and risk of head and neck squamous cell carcinomas in a Chinese population.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are one of the most common cancers in the world, and nucleotide excision repair (NER) is involved in HNSCCs susceptibility. We investigated whether mRNA expression levels of nine core NER genes were associated with risk of HNSCCs in a Chinese population. METHODS: In this study of 251 HNSCC patients and 232 healthy controls, we quantified NER gene mRNA expression levels in cultured peripheral lymphocytes using a quantitative real-time PCR. RESULTS: Compared with the controls, HNSCC patients had statistically significantly lower expression levels of XPA and XPB (P = 0.029 and 0.001, respectively). After dividing the subjects by the controls' median values of expression levels, we found a dose-dependent association between an increased risk of HNSCCs and low expression levels of XPB (adjusted OR 1.56 and 95% CI 1.07-2.28; Ptrend = 0.001). We also identified a significant multiplicative interaction between smoking status as well as alcohol status and mRNA expression levels of XPB (P = 0.014 and 0.042, respectively). Finally, after integrating demographic variables, we found the addition of smoking status and XPB expression levels to the model significantly improved the sensitivity of the expanded model on HNSCC risk. CONCLUSION: Reduced mRNA expression levels of XPB were associated with an increased risk of HNSCCs in a Chinese population.

Do carbon nanoparticles really improve thyroid cancer surgery? A retrospective analysis of real-world data.

BACKGROUND: Parathyroid protection and central neck dissection (CND) are basic points of thyroid cancer surgery and draw persistent concern. We aimed to evaluate the value of carbon nanoparticles (CNs) for parathyroid gland protection and CND in thyroid surgery for thyroid cancer patients. METHODS: A total of 386 consecutive thyroid cancer patients were enrolled in the retrospective study. Three hundred thirty-four patients using CNs intraoperatively were included in the CN group, and 52 patients without using CNs or any other helping agent were included in the control group. Intact parathyroid hormone (iPTH) was examined. Medical records and histopathologic reports were reviewed. Histopathologic examination was performed. RESULTS: There were no statistical significances in demographic and basic surgical information, preoperative iPTH, and serum calcium between the two groups (P > 0.05). In the CN group, the thyroid tissue and central neck lymph nodes were stained black by CNs, while the parathyroid glands were not. Histopathological examination showed that the carbon nanoparticles might accumulated in the subcapsular sinus of lymph nodes compared with the none-stained samples. The staining with CNs did not impact the histopathological examination. There were no significant differences in postoperative hypocalcemia and hypoPT at day 1, 1 month, and half year after surgery between the two groups, respectively. There was a big decline of iPTH level after surgery, whereas the perioperative decreasing amplitude of PTH was not statistically different between the CNs and control group (57.2 ± 28.6 vs 55.7 ± 27.8, P = 0.710). There were 43 patients occurring incidental parathyroidectomy in the CN group (43/334, 12.9%) and 7 patients in the control group (7/52, 13.5%), without significant difference (P = 0.907). There was no significant difference in the number of lymph nodes identified by pathology per patient between the CNs and control group regardless of unilateral and bilateral CND. CONCLUSIONS: Carbon nanoparticles help highlight parathyroid glands and lymph nodes in thyroidectomy, but generate no significant benefit for parathyroid glands protection and lymph node dissection. The value of carbon nanoparticles in thyroid cancer surgery should not be exaggerated and needs further evaluation.

Association of SNPs in the OBFC1 gene and laryngeal carcinoma in Chinese Han male population.

BACKGROUND: Laryngeal carcinoma (LC) is one of common diagnosed head and neck malignancies. Telomere length has been reported involved in malignant transformation and tumorigenesis. We speculate that single nucleotide polymorphisms (SNPs) in telomere length-related gene oligonucleotide/oligosaccharide-binding folds containing 1 (OBFC1) may have an association with LC in Chinese Han male population. METHODS: To prove this hypothesis, we performed a case-control study to analyze the OBFC1 polymorphisms in 172 LC patients and 180 healthy controls. A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping. RESULTS: There was a significant difference in rs9325507 T allele frequency (OR = 0.88, 95% CI 0.64-1.21, P = 0.036) and rs11191865 A allele frequency (OR = 0.86, 95% CI 0.62-1.18, P = 0.009) between patient and control groups. In addition, the rs9325507 T/C genotype, rs3814220 G/A genotype, rs12765878 C/T genotype and rs11191865 A/G genotype had a lower risk of LC based on the results of logistic regression model analysis. CONCLUSIONS: The results indicate a potential association between OBFC1 and LC risk in Chinese Han male population. Further work is required to confirm these results and explore the mechanisms of these effects.

Novel pretreatment nomograms based on pan-immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma.

Background: The prognostic value of an effective biomarker, pan-immune-inflammation value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients. Methods: A total of 161 HNSCC patients who underwent radical surgery were enrolled retrospectively for development cohort. The cutoff of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS). The concordance index, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to evaluate the nomograms. A cohort composed of 50 patients who received radiotherapy or chemoradiotherapy (RT/CRT) alone was applied for generality testing of PIV and nomograms. Results: Patients with higher PIV (≥123.3) experienced a worse DFS (HR, 5.01; 95% CI, 3.25-7.72; p<0.0001) and overall survival (OS) (HR, 5.23; 95% CI, 3.34-8.18; p<0.0001) compared to patients with lower PIV (<123.3) in the development cohort. Predictors of Model A included age, TNM stage, neutrophil-to-lymphocyte ratio (NLR), and PIV, and that of Model B included TNM stage, lymphocyte-to-monocyte ratio (LMR), and PIV. In comparison with TNM stage alone, the two nomograms demonstrated good calibration and discrimination and showed satisfactory clinical utility in internal validation. The generality testing results showed that higher PIV was also associated with worse survival outcomes in the RT/CRT cohort and the possibility that the two nomograms may have a universal applicability for patients with different treatments. Conclusions: The nomograms based on PIV, a simple but useful indicator, can provide prognosis prediction of individual HNSCC patients after radical surgery and may be broadly applicated for patients after RT/CRT alone.

The Feasibility Study of Intraoperative RLN Monitoring Using Cricothyroid Membrane-Inserted Needle Electrodes During Thyroid Surgery.

OBJECTIVE: This study evaluated the feasibility, stability, safety, and economy of cricothyroid membrane (CM)-inserted needle electrodes for recurrent laryngeal nerve monitoring. STUDY DESIGN: Parallel and controlled study. SETTING: Clinical research center for thyroid diseases of Shaanxi province. METHODS: A total of 64 patients in the needle electrodes group (104 recurrent laryngeal nerves [RLNs]) and 44 patients in the endotracheal tube (ETT)-based electrodes group (80 RLNs) underwent monitored thyroidectomy. The evoked electromyography (EMG) signals detected by the 2 electrodes were recorded and analyzed. The changes in EMG during Berry's ligament traction and tracheal displacement were compared. All patients underwent preoperative and postoperative laryngoscopy within 1 week. RESULTS: Both electrodes successfully recorded typical evoked laryngeal EMG waveforms from RLNs. The needle electrodes recorded relatively higher amplitudes and similar latencies compared to ETT-based electrodes. The evoked EMG signals attributed to needle electrodes could accurately predict the function of RLNs with 100% sensitivity and specificity. The reduction in the recorded amplitudes attributed to needle electrodes was higher than that observed with ETT-based electrodes during Berry's ligament traction or trachea displacement, whereas a similar increase in the latencies was recorded in the 2 groups. Particularly, Berry's ligament traction was more likely to lead to EMG amplitude reduction and latency prolongation. The needle electrodes group recorded 2 cases of minor bleeding on the CM. The needle electrodes were more cost-effective than ETT-based electrodes. CONCLUSION: The CM-inserted needle electrodes are feasible, stable, safe, and economical for RLN monitoring, and they provide an alternative novel intraoperative neural monitoring format for thyroid surgeons.

Genetic Variation in the ZNF208 Gene at rs8103163 and rs7248488 Is Associated With Laryngeal Cancer in the Northwestern Chinese Han Male.

Background: Laryngeal cancer is more common in middle-aged and older men. We conducted an association analysis between ZNF208 polymorphisms and laryngeal cancer (LC) risk in the Northwestern Chinese Han male. Methods: A total of 352 subjects (172 LC patients and 180 controls) were involved in this study. Agena MassARRAY was used to determine the genotypes. Unconditional logistic regression analysis was performed to explore the relevance. Results: Two SNPs were associated with the risk of LC: rs8103163, OR = 1.41, p = 0.043; rs7248488, OR = 1.45, p = 0.025. Furthermore, rs8103163 was associated with an increased risk of LC under a log-additive model (OR = 1.40, p = 0.042), and rs7248488 was related to a higher risk of LC under a recessive model (OR = 2.33, p = 0.025) and a log-additive model (OR = 1.44, p = 0.026). Conclusions: We first demonstrated that the rs8103163 A allele and the rs7248488 A allele in ZNF208 create susceptibility to laryngeal cancer in the Northwestern Chinese Han male.

The effect of VAV3 polymorphisms on thyroid cancer.

BACKGROUND: The incidence of thyroid cancer is rising rapidly in China, but there are few studies on the risk factors of thyroid cancer in the Chinese Han population. METHODS: We performed this case-control study of 510 patients and 509 controls to for determine the linkage of VAV3 variants (rs17019602, rs7521681, rs4915076, and rs1777451) with thyroid cancer susceptibility by computing the odds ratio (OR) and 95% confidence intervals (CI). Multi-factor dimension reduction (MDR) analysis was conducted to assess interaction of VAV3 genetic variants. RESULTS: We found that rs7521681 was remarkably related to a higher risk of thyroid cancer (OR = 1.74, p = 0.012), whereas rs4915076 (OR = 0.66, p = 0.001) significantly decreased thyroid cancer susceptibility. Stratified analyses showed that rs4915076 had a protective role in thyroid cancer in both ages >45 years (OR = 0.70, p = 0.017) and age ≤45 years (OR = 0.63, p = 0.007). Rs17019602 could increase the susceptibility of thyroid cancer in men (OR = 4.76, p = 0.049). Rs7521681 was related to an increased risk of thyroid cancer in women (OR = 1.97, p = 0.012). Rs4915076 could protect individuals from thyroid cancer both in men (OR = 0.60, p = 0.031) and women (OR = 0.68, p = 0.010). Moreover, rs4915076 was the best single-locus model to predict thyroid cancer. Interestingly, the interaction model of rs17019602, rs7521681, rs4915076, rs1777451, and age was a candidate gene-environment model. CONCLUSION: Our results indicated VAV3 variants were associated with thyroid cancer, which provides a new sight into etiology of thyroid cancer.

Downregulation of TMEM220 promotes tumor progression in Hepatocellular Carcinoma.

During the process of long-term carcinogenesis, cells accumulate many mutations. Deregulated genes expression causes profound changes in cell proliferation, which is one of the hallmarks of HCC. A comprehensive understanding of these changes will contribute to the molecular mechanism of HCC progression. Through clinical sample analysis, we found that TMEM220 is downregulated in tumor and lower levels of TMEM220 is associated with poor prognosis in HCC patients. Through overexpressing TMEM220 in HCC cell lines, we found that the proliferation of cancer cells was significantly slowed down and metastasis was significantly reduced. For further study of its molecular mechanism, we performed a reverse-phase protein array (RPPA). The results suggest that phenotypic changes caused by TMEM220 in HCC cells might be associated with FOXO and PI3K-Akt pathways. Mechanism studies showed that overexpression of TMEM220 could regulate ß-catenin and FOXO3 transcriptional activity by altering their subcellular localization, affecting the expression of downstream gene p21 and SNAIL, and ultimately reducing the progression of HCC. Altogether, our study proposes a working model in which upregulation of TMEM220 expression alters the genes expression involved in cell proliferation, thereby inhibiting HCC progression, which suggests that TMEM220 might serve as a clinical biomarker.

Targeting EIF3C to suppress the development and progression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma occurs in many parts of the pars nasalis pharyngis, and the pathological type is mainly squamous cell carcinoma. Because of the special position of nasopharynx, breathing, pronunciation and daily life will be seriously affected. At present, the research direction of nasopharyngeal carcinoma is mainly to explore the law of tumor cell proliferation and migration, study the molecular mechanism, master its biological behavior and clinical significance, try to find therapeutic targets, and further improve the level of tumor treatment. However, the pathologic structure and molecular mechanism of nasopharyngeal carcinoma have not been fully elucidated. In this study, the Lentivirus-mediated EIF3C shRNA vector (L.V-shEIF3C) was constructed to down-regulate the expression of EIF3C in human pharyngeal squamous carcinoma cell FaDu and the human nasopharyngeal carcinoma cell 5-8F, it was found that down-regulation of EIF3C could significantly inhibit the cell proliferation, promote cell apoptosis, induce cell cycle arrest, and inhibit the formation and growth of tumors in mouse models. This study provides strong evidence that EIF3C is a key gene driving the development and progression of head and neck cancer, which is of great significance for the diagnosis, prognosis or treatment of tumors, suggesting that EIF3C may become a valuable therapeutic development and intervention target.

Evaluation of integrin αvß3-targeted imaging for predicting disease progression in patients with high-risk differentiated thyroid cancer (using 99mTc-3PRGD2).

BACKGROUND: High-risk differentiated thyroid cancer (DTC) needs effective early prediction tools to improving clinical management and prognosis. This cohort study aimed to investigate the prognostic impact of 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) SPECT/CT in high-risk DTC patients after initial radioactive iodine (RAI) therapy. METHODS: Thirty-three patients with high-risk DTC were prospectively recruited; all patients underwent total thyroidectomy and received 99mTc-3PRGD2 SPECT/CT before RAI ablation. Follow-up was done with serological and imaging studies. The correlation between 99mTc-3PRGD2 avidity and remission rate for initial RAI therapy was evaluated using logistic regression analysis. The prognostic value of 99mTc-3PRGD2 SPECT/CT was evaluated by Kaplan-Meier curve and Cox regression analysis. RESULTS: 99mTc-3PRGD2 avidity was significantly correlated with the efficacy of initial RAI ablation and an effective predictor for non-remission in high-risk DTC (OR = 9.36; 95% CI = 1.10-79.83; P = 0.041). 99mTc-3PRGD2 avidity was associated with poor prognosis in patients with high-risk DTC and an independent prognostic factor for shorter progression-free survival (PFS) (HR = 9.47; 95% CI = 1.08-83.20; P = 0.043). Survival analysis, which was performed between DTC patients with concordant (131I positive/99mTc-3PRGD2 positive) and discordant (131I negative/99mTc-3PRGD2 positive) lesions, indicated that patients with concordant lesions had significantly better PFS than those with discordant lesions (P = 0.022). Moreover, compared with repeated RAI, additional surgery or targeted therapy with multikinase inhibitors could lead to a higher rate of remission in 99mTc-3PRGD2-positive patients with progressive disease. CONCLUSIONS: 99mTc-3PRGD2 SPECT/CT is a useful modality in predicting progression of the disease after initial RAI and guiding further treatment in high-risk DTC patients.

Long non-coding RNA AGAP2-AS1 promotes cell proliferation and invasion through regulating miR-193a-3p/LOXL4 axis in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is an aggressive malignancy with highly mortality rate. Long non-coding RNA (lncRNA) AGAP2-AS1 is an identified oncogene in several types of cancers. However, the role of AGAP2-AS1 in LSCC remains unclear. The expression levels of AGAP2-AS1 in LSCC tissues and cell lines were measured using qRT-PCR. AGAP2-AS1 was knocked down in LSCC cells through transfection with siRNA-AGAP2-AS1. Cell proliferation and invasion were detected using MTT and transwell assays. Dual-luciferase reporter gene assay was performed to confirm the interaction with AGAP2-AS1 and downstream genes. Our results showed that AGAP2-AS1 expression was remarkably increased in human LSCC tissues and cell lines. Knockdown of AGAP2-AS1 significantly inhibited the proliferation and invasion of LSCC cells. In addition, AGAP2-AS1 sponged miR-193a-3p and regulated its expression in LSCC cells. Inhibition of miR-193a-3p reversed the effects of AGAP2-AS1 knockdown on LSCC cells. Furthermore, Lysyl oxidase-like 4 (LOXL4) was a target gene of miR-193a-3p and the role of miR-193a-3p was mediated by LOXL4. In conclusion, these findings suggest that knockdown of AGAP2-AS1 inhibited the proliferation and invasion of LSCC cells through regulating the miR-193a-3p/LOXL4 axis.

The Genetic Polymorphisms in the MIR17HG Gene Are Associated with the Risk of Head and Neck Squamous Cell Carcinoma in the Chinese Han Population.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumors in the world. Genetic variants have an important role in HNSCC progression. Our study is aimed at exploring the relationship between MIR17HG polymorphisms and HNSCC risk in the Chinese Han population. METHODS: We recruited 537 HNSCC cases and 533 healthy subjects to detect the correlation of six polymorphisms in MIR17HG with HNSCC susceptibility. The associations were evaluated by computing odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analysis. RESULTS: Our study revealed that rs7336610 (OR 1.77, 95%CI = 1.09-2.86, and p = 0.021) and rs1428 (OR 1.73, 95%CI = 1.07-2.81, and p = 0.025) are strongly associated with increased susceptibility to HNSCC in men. Besides, rs17735387 played a crucial protective role in stage III/IV HNSCC patients (OR 0.34, 95%CI = 0.12-0.95, and p = 0.040) compared with stage I/II. CONCLUSION: Our study firstly indicated that MIR17HG polymorphisms are significantly associated with HNSCC susceptibility, which suggests that MIR17HG has a potential role in the occurrence of HNSCC.

Downregulation of microR-147b represses the proliferation and invasion of thyroid carcinoma cells by inhibiting Wnt/ß-catenin signaling via targeting SOX15.

microRNA-147b (miR-147b) is a newly identified tumor-related miRNA that is dysregulated in multiple cancer types. Yet, the role of miR-147b in thyroid carcinoma remains unknown. Herein, we found that miR-147b expression was upregulated in thyroid carcinoma tissues and cell lines. miR-147b inhibition decreased the proliferation, colony formation, and invasion of thyroid carcinoma cells. The tumor suppressive gene SRY-related high-mobility-group box gene 15 (SOX15) was predicted as a miR-147b target gene. SOX15 expression was markedly decreased in thyroid carcinoma tissues and inversely correlated with the miR-147b expression. SOX15 overexpression repressed the proliferation and invasion of thyroid carcinoma cells associated with downregulation of Wnt/ß-catenin signaling. SOX15 knockdown abolished the miR-147b-inhibition-mediated antitumor effect. miR-147b inhibition or SOX15 overexpression retarded the tumor growth of thyroid carcinoma cells in vivo. Overall, our study suggests that miR-147b inhibition restrains the proliferation and invasion of thyroid carcinoma cells through upregulation of SOX15 and inhibition of Wnt/ß-catenin signaling.

[Resveratrol increases sensitivity of CNE2 cells to chemotherapeutic drugs under hypoxia].

OBJECTIVE: To explore the sensitization effects of resveratrol on CNE2 nasopharyngeal carcinoma cell line with hypoxia-induced chemotherapy resistance and the potential mechanism. METHODS: Human CNE2 nasopharyngeal carcinoma cell line was cultured under hypoxic conditions (37 degrees centigrade, 5% CO(2), 2% O(2)) in vitro. The cultured cells were treated with different concentrations of resveratrol for 48 h. Reversal fold (RF) of reseratrol to chemotherapeutic drugs in CNE2 cells was measured by methyl thiazolyl tetrazolium (MTT) assay. Apoptotic rate of CNE2 cells was observed by flow cytometry. Reverse transcription-polymerase chain reaction (RT-PCR) method and Western blotting were used to investigate the expressions of multidrug resistance gene 1 (mdr1), multidrug resistance-associated protein 1 (MRP1) and hypoxia inducible factor 1alpha (HIF-1alpha) in CNE2 cells. RESULTS: Resveratrol combined with chemotherapeutics produced a synergistic effect. The RF of 200 micromol/L resveratrol to paclitaxel was 2.58. Combined with paclitaxel, 25, 50, 100 and 200 micromol/L of resveratrol increased the apoptotic rate of CNE2 cells from (22.14+/-1.09)% to (23.24+/-1.37)%, (27.57+/-2.01)%, and (30.36+/-2.31)%, respectively. Resveratrol could down-regulate the expressions of HIF-1alpha, mdr1 and MRP1 significantly. After being treated with resveratrol at different concentrations separately, the expressions of HIF-1alpha, mdr1 and MRP1 in CNE2 cells decreased significantly as compared with paclitaxel alone or paclitaxel plus verapamil (P<0.01). CONCLUSION: Resveratrol can enhance the sensitivity of CNE2 cells to chemotherapeutic drugs under hypoxia. The potential mechanism is partly attributed to inhibiting the gene expressions of HIF-1alpha, mdr1 and MRP1.

MEIS2C and MEIS2D promote tumor progression via Wnt/ß-catenin and hippo/YAP signaling in hepatocellular carcinoma.

BACKGROUND: MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. METHODS: The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. RESULTS: The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/ß-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/ß-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. CONCLUSIONS: Our studies indicate that MEISC/D promote HCC development via Wnt/ß-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.

Gender-Specific Risk of Central Compartment Lymph Node Metastasis in Papillary Thyroid Carcinoma.

Our aim was to evaluate the impact of gender on the predictive factors of central compartment lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC). A retrospective study of 590 patients treated for PTC was performed. Univariate and multivariate analyses showed that gender (female; P = 0.001), age (≥45 y; P < 0.001), tumor size (>1 cm; P < 0.001), and multifocality (P = 0.004) were independent predictive factors of CLNM in PTC patients. Patients were divided into male group (n = 152) and female group (n = 438). Age (≥45 y; P = 0.001), T4 (P = 0.006) and multifocality (P = 0.024) were independent predictive risk factors of CLNM in male patients. As for female patients, age (≥45 y; P < 0.001), tumor size (>1 cm; P < 0.001), multifocality (P = 0.002), and microcalcification (P = 0.027) were independently correlated with CLNM. The sensitivity of the multivariate model for predicting CLNM in male patients was 64.9%, specificity was 82.9%, and area under the ROC curve (AUC) was 0.764. As for female patients, the sensitivity was 55.7%, specificity was 77.9%, and AUC was 0.73. This study showed that the predictive factors of CLNM indeed varied according to gender. To have a more accurate evaluation of CLNM, different predictive systems should be used for male and female patients.

Recombinant adeno-associated virus expressing a p53-derived apoptotic peptide (37AA) inhibits HCC cells growth in vitro and in vivo.

Recent studies have confirmed that a p53-derived apoptotic peptide (37AA) could act as a tumor suppressor inducing apoptosis in multiple tumor cells through derepressing p73. However, the tumor suppressive effects of recombinant adeno-associated virus (rAAV) expressing 37AA on HCC cells are still unknown. In this study, we successfully constructed a recombinant rAAV expressing 37AA. In vitro and in vivo assays showed that transfection of NT4-37AA/rAAV in HCC cells strongly suppressed cell proliferation, induced apoptosis, and up-regulated the cellular expression of p73. NT4-37AA/rAAV transfection markedly slowed Huh-7 xenografted tumor growth in murine. Pretreatment of HCC cells with p73 siRNA abrogated these effects of NT4-37AA/rAAV. Furthermore, we found that expression of p73 was upregulated and the formation of P73/iASSP complex was prevented when 37AA was introduced into HCC cells. Taken together, these results indicate that introduction of 37AA into HCC cells with a rAAV vector may lead to the development of broadly applicable agents for the treatment of HCC, and the mechanism may, at least in part, be associated with the upregulation of p73 expression and reduced level of P73/iASSP complex.