Minghua Ge

Clinical Characteristics Related to Central Lymph Node Metastasis in cN0 Papillary Thyroid Carcinoma: A Retrospective Study of 916 Patients

Background. Papillary thyroid carcinoma (PTC) is a form of thyroid cancer with high risk of cervical lymph node metastasis. Aim. The aim of this study was to investigate the incidence and the predictive factors for occult ipsilateral central lymph node (CLN) metastasis in the patients with papillary thyroid carcinoma. Methods. A total of 916 PTC patients (1017 lesions) undergoing central lymph node dissection in our hospital from 2005 to 2011 were enrolled. The relationship between CLN metastasis and clinical factors such as gender, age, tumor size, tumor number, capsule invasion, and tumor location was analyzed. Results. Occult CLN metastasis was observed in 52.41% (533/1017) of PTC lesions, respectively. Multivariate analysis showed that age ≤ 35 years, tumor size > 1.5 cm, present capsule invasion/extracapsular invasion, and tumor located in upper/middle pole/whole lobe were risk factors of CLN metastasis. Conclusions. Tumor located in upper/middle pole/whole lobe, less than 35 years old, tumor size > 1.5 cm, and present capsule invasion/extracapsular invasion were risk factors of CLN metastasis. We recommend performing ipsilateral prophylactic CLN dissection in cN0 PTC patients.

Fbxw7 Tumor Suppressor: A Vital Regulator Contributes to Human Tumorigenesis.

AbstractRapidly accumulating data indicate that F-box/WD repeat-containing protein 7 (Fbxw7) is one of the most frequently mutated genes in human cancers and regulates a network of crucial oncoproteins. These studies have generated important new insights into tumorigenesis and may soon enable therapies targeting the Fbxw7 pathway.We searched PubMed, Embase, and ISI Web of Science databases (1973–2015, especially recent 5 years) for articles published in the English language using the key words “Fbxw7,” “Fbw7,” “hCDC4,” and “Sel-10,” and we reviewed recent developments in the search for Fbxw7.Fbxw7 coordinates the ubiquitin-dependent proteolysis of several critical cellular regulators, thereby controlling essential processes, such as cell cycle, differentiation, and apoptosis. Fbxw7 contains 3 isoforms (Fbxw7&agr;, Fbxw7&bgr;, and Fbxw7&ggr;), and they are differently regulated in subtract recognition. Besides those, Fbxw7 activity is controlled at different levels, resulting in specific and tunable regulation of the abundance and activity of its substrates in a variety of human solid tumor types, including glioma malignancy, nasopharyngeal carcinoma, osteosarcoma, melanoma as well as colorectal, lung, breast, gastric, liver, pancreatic, renal, prostate, endometrial, and esophageal cancers.Fbxw7 is strongly associated with tumorigenesis, and the mechanisms and consequences of Fbxw7 deregulation in cancers may soon enable the development of novel therapeutic approaches.

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma.

miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients.

Pim-1 acts as an oncogene in human salivary gland adenoid cystic carcinoma

BackgroundPim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed.MethodsSACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells’ invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry.ResultsPim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues.ConclusionsThis study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer.

Clinicopathological features and prognosis of familial papillary thyroid carcinoma--a large-scale, matched, case-control study.

It remains controversial whether or not the aggressiveness of familial nonmedullary thyroid cancer (FNMTC) differs from sporadic carcinoma. The aim of this study was to determine the clinicopathological features and prognosis of FNMTC.

Abnormal Expression of DNA Double-Strand Breaks Related Genes, ATM and GammaH2AX, in Thyroid Carcinoma

ATM and γH2AX play a vital role in the detection of DNA double-strand breaks (DSB) and DNA damage response (DDR). This study aims to investigate ATM and γH2AX expression in thyroid cancer and discuss possible relationship between thyroid function tests and DNA damage. The expression of ATM and γH2AX was detected by immunohistochemistry in 30 cases of benign nodular goiter, 110 cases of well differentiated thyroid cancer, 22 cases of poorly differentiated thyroid cancer, and 21 cases of anaplastic thyroid cancer. Clinicopathological features, including differentiation stages, distant metastasis, lymph node metastasis, T classification, TNM stage, and tests of thyroid functions (TPOAb, Tg Ab, T3, FT3, T4, FT4, TSH, and Tg), were reviewed and their associations with γH2AX and ATM were analyzed. γH2AX and ATM expressed higher in thyroid cancer tissues than in benign nodular goiter and normal adjacent tissues. γH2AX was correlated with ATM in thyroid cancer. Both γH2AX and ATM expression were associated with FT3. γH2AX was also associated with T classification, TNM stage, FT4, TSH, and differentiation status. Therefore both of ATM and γH2AX seem to correlate with thyroid hormones and γH2AX plays a role in the differentiation status of thyroid cancer.

Prognostic significance of p53 immunohistochemical expression in adenoid cystic carcinoma of the salivary glands: a meta-analysis

Adenoid cystic carcinoma of salivary glands is a rare adenocarcinoma and has been placed in “high-risk” category as poor long-term prognosis. The purpose of this study was to investigate p53 protein expression in adenoid cystic carcinoma of salivary glands and its correlation with clinicopathological parameters and prognosis. Literatures were searched from PubMed, Embase, Cochrane Library and Web of Science, which investigated the relationships between p53 expression and pathological type, clinical stage, local recurrence, metastasis, nerve infiltration and overall survival. A total of 1,608 patients from 36 studies were included in the analysis. The results showed that p53-postive expression rate was 49% in adenoid cystic carcinoma of salivary glands (OR=10.34, 95%CI: 4.93-21.71, P < 0.0001). The p53-postive expression was closely related to tumor types (OR=0.30, 95%CI: 0.14-0.65, P < 0.0001). The tumor with solid histological subtype had a strong positive correlation with p53 expression. The combined analysis revealed that the p53-positive expression rate among patients in T1and T2 stage was 41.4%, compared to 53.2% among those in T3 and T4 stage. However, there was no significant correlation between tumor stage and p53 expression (OR=0.47, 95% CI: 0.17-1.29, P = 0.14). Besides, compared to patients with p53-negative expression, those with p53-positive expression had a greater chance of developing metastasis, local recurrence and nerve infiltration as well as poorer 5-year overall survival (P < 0.01). In conclusion, the p53 expression is related to the survival of adenoid cystic carcinoma of salivary glands. It can be considered as the auxiliary detection index in treatment and prognosis of adenoid cystic carcinoma of salivary glands.

Vascular invasion is an independent prognostic factor for distant recurrence-free survival in papillary thyroid carcinoma: a matched-case comparative study

Objective It is still unclear whether the clinicopathological and outcome characteristics of vascular invasion (VI) (+) papillary thyroid carcinoma (PTC) differ from VI (−) PTC. This study aims to establish distinguishing features of patients with VI (+) and VI (−) PTC and to investigate the biological and clinical aggressiveness of the disease in these patient groups. Design A matched-case comparative study. Methods 412 patients (VI (+) PTC study group n=103, and VI (−) PTC control group n=309). These two patient groups were matched 1:3 for variables of age, gender, histological variants, tumour/node/metastasis (TNM) staging and approximate duration of follow-up. Clinicopathological factors and prognosis were compared across the two patient groups. Results The median age at the time of diagnosis was 42.0 years, and 68.9% were females. Across the patient groups, the incidence of tumour multifocality in patients with VI (+) PTC was slightly higher than in those with VI (−) PTC (p=0.049). In addition, when undergoing more aggressive therapy regimens patients with VI (+) PTC showed decreased distant recurrence-free survival (DRFS), but not regional recurrence-free survival (RRFS) and disease-specific survival (DSS) compared with patients who were VI (−). VI was found to be an independent predictor of DRFS, combined with tumour size >3 cm and total thyroidectomy. Conclusions VI was an independent risk factor for DRFS, necessitating the need for appropriate postoperative treatment and careful follow-up.

The Landscape of Circular RNA Expression Profiles in Papillary Thyroid Carcinoma Based on RNA Sequencing

Background/Aims: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, the molecular mechanisms responsible for its tumorigenesis and progression remain largely unknown. Circular RNA (circRNA) is a novel type of noncoding RNA that can serve as an ideal biomarker due to its stability. Recent evidence suggests that circRNAs play important roles in tumorigenesis. This study aims to investigate circRNA expression profiles and their potential biological functions in PTC. Methods: High-throughput RNA sequencing was used to assess circRNA expression profiles in PTC, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate dysregulated circRNAs. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of circRNAs for PTC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed circRNAs. Bioinformatic analyses were applied to predict interactions between circRNAs and microRNAs (miRNAs), and a circRNA-miRNA-mRNA network was constructed using Cytoscape software. Results: We identified a number of differentially expressed circRNAs in PTC tissues compared with paired normal thyroid tissues, with chr5: 160757890-160763776–, chr12: 40696591-40697936+, chr7: 22330794-22357656-, and chr21: 16386665-16415895– being upregulated, and chr7: 91924203-91957214+, chr2: 179514891-179516047–, chr9: 16435553-16437522–, and chr22: 36006931-36007153– being downregulated. These findings were confirmed by qRT-PCR, and ROC curves indicated that they can serve as potential biomarkers for PTC. GO and KEGG pathway analyses showed that some of these circRNAs are related to cancers. Additionally, bioinformatic analyses revealed a potential competing-endogenous-RNA-regulating network among circRNAs, miRNAs, and mRNAs. Conclusions: Our study results depict the landscape of circRNA expression profiles in PTC and also provide potential biomarkers for PTC. Further functional and mechanistic studies of these circRNAs may improve our understanding of PTC tumorigenesis.

Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776

ABSTRACT Provirus integration site for Moloney murine leukemia virus 1 (Pim‐1) has proved to be an oncogene and it is known that to depress Pim‐1 activity may be a novel oncological treatment strategy. SGI‐1776, a small molecule, is the first clinically tested inhibitor of the Pim kinase family. Here, we aimed to explore the effect of SGI‐1776 on salivary adenoid cystic carcinoma (SACC). Expression of Pim‐1 was confirmed in SACC and control tissues by qRT‐PCR. After SGI‐1776 treatment, the Pim‐1 expressions and Pim‐1 kinase activity in both SACC‐83 and SACC‐LM cell lines were measured. Cell proliferation, cell invasion, cell cycle, apoptosis and mitochondrial membrane potential were analyzed. Also, the expression of FOXO3a, p‐FOXO3a, RUNX3, Bcl‐2, BAD, p‐BAD, Bim and p‐Bim were detected by Western blot. The results showed that Pim‐1 was significantly overexpressed in SACC tissues. SGI‐1776 down‐regulated the Pim‐1 expression, inhibited Pim‐1 kinase activity, reduced cell proliferation, decreased invasive ability, increased caspase‐3 activity and induced apoptosis, cell cycle arrest and mitochondrial depolarization. Reduced expression was also seen in p‐FOXO3a, RUNX3, Bcl‐2, p‐BAD and p‐Bim, whereas no significant changes were observed from FOXO3a, BAD and Bim. These results confirm the pivotal role of Pim‐1 in SACC and suggest that targeting Pim‐1 kinase signal pathway by SGI‐1776 might be a promising therapeutic modality for SACC.