Indoleamine 2,3-dioxygenase 2 immunohistochemical expression in medullary thyroid carcinoma: implications in prognosis and immunomodulatory effects.

BACKGROUND: The linkage between IDO2 expression and cancer progression is still unclear, particularly in medullary thyroid carcinoma (MTC). Our purpose is to unveil the potential correlations between IDO2 status, clinical-pathological parameters, patients' prognosis, and the possible immunomodulatory functions in MTC. METHODS: Immunohistochemical expression levels of IDO2 were evaluated in the resected MTC surgical specimens and corresponding lymph nodes. CD4 + T cell infiltration was also evaluated by immunohistochemical analysis in the MTC tissues. The association of the IDO2 expression level with clinicopathologic characteristics, overall survival (OS)/recurrence-free survival (RFS), and CD4 + T cell infiltration were retrospectively investigated. RESULTS: High expression of IDO2 is closely associated with more aggressive clinicopathological features, such as multifocality, ETE, a higher pT stage and especially a higher pN stage. Moreover, a significant difference in RFS was observed between the IDO2-high and IDO2-low groups. IDO2 expression of lymph node tissues was significantly related to the metastasis status. Furthermore, we found that IDO2 expression is negatively correlated with CD4 + T cell infiltrations in MTC tissues. CONCLUSION: The expression level of IDO2 is associated with aggressive characteristics and is predictive of poor prognosis in patients with MTC. Also, an interesting observation is that IDO2 involvement in MTC showed a moderate sexual dimorphism, of which female patients tend to be more affected by IDO2 status. Moreover, our results showed the potential immunomodulatory functions of IDO2. The close relationship between IDO2 and CD4 + T cell infiltration in the MTC microenvironment, together with its potential prognostic implications, makes it possible for IDO2 to serve as an alternative drug target in cancer immunotherapy and as a new prognostic tool.

Loss of PTEN Expression Is Associated With High MicroRNA 24 Level and Poor Prognosis in Patients With Tongue Squamous Cell Carcinoma.

PURPOSE: The aim of this study was to detect the relationship between phosphatase and tensin homolog deletion on chromosome 10 (PTEN) and microRNA 24 (miR-24) and correlate PTEN expression with important clinical parameters of patients with tongue squamous cell carcinoma (TSCC). MATERIALS AND METHODS: In this retrospective case series, all TSCC patients treated at Tianjin Medical University Cancer Institute and Hospital between March 2005 and October 2011 were retrospectively reviewed. Demographic information and clinical data (histologic type, clinical stage, tumor differentiation, and so on) were collected. The miR-24 level was detected by quantitative reverse transcription-polymerase chain reaction. The PTEN level was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Data analyses were performed by Spearman correlation analysis, Pearson χ2 test, and paired t test. Kaplan-Meier curves, log-rank analyses, and a Cox proportional hazards model were used to evaluate the prognostic value of PTEN. RESULTS: A total of 90 patients (aged 59.4 ± 9.5 years, 53 men and 37 women) were identified. Loss of PTEN expression was detected in 27 of 90 tumors (30%)" in both occurrences [corrected]. The PTEN messenger RNA level was negatively correlated with the miR-24 level (r = -0.569, P < .01). PTEN expression also was negatively correlated with the miR-24 level (r = -0.621, P < .01). Furthermore, PTEN expression was significantly lower in cancer tissues than in adjacent normal tissues, and its expression was negatively correlated with clinical stage (P < .01) and positively correlated with differentiation (P < .05) in TSCC patients. In addition, the Kaplan-Meier curve indicated that loss of PTEN expression resulted in poor survival of TSCC patients (P < .01). Multivariate analysis indicated that PTEN expression level and clinical stage may be independent prognostic factors for TSCC patients. CONCLUSIONS: This study suggested that PTEN expression was negatively correlated with the miR-24 level in TSCC. The loss of PTEN expression may serve as a predictor of unfavorable prognosis for TSCC patients.

Twist1 expression induced by sunitinib accelerates tumor cell vasculogenic mimicry by increasing the population of CD133+ cells in triple-negative breast cancer.

BACKGROUND: Hypoxia induced by antiangiogenic agents is linked to the generation of cancer stem cells (CSCs) and treatment failure through unknown mechanisms. The generation of endothelial cell-independent microcirculation in malignant tumors is defined as tumor cell vasculogenic mimicry (VM). In the present study, we analyzed the effects of an antiangiogenic agent on VM in triple-negative breast cancer (TNBC). METHODS: Microcirculation patterns were detected in patients with TNBC and non-TNBC. Tientsin Albino 2 (TA2) mice engrafted with mouse TNBC cells and nude mice engrafted with human breast cancer cell lines with TNBC or non-TNBC phenotypes were administered sunitinib and analyzed to determine tumor progression, survival, microcirculation, and oxygen concentration. Further, we evaluated the effects of hypoxia induced with CoCl2 and the expression levels of the transcription factor Twist1, in the presence or absence of a Twist siRNA, on the population of CD133(+) cells and VM in TNBC and non-TNBC cells. RESULTS: VM was detected in 35.8 and 17.8% of patients with TNBC or with non-TNBC, respectively. The growth of tumors in TNBC and non-TNBC-bearing mice was inhibited by sunitinib. The tumors in TA2 mice engrafted with mouse TNBCs and in mice engrafted a human TNBC cell line (MDA-MB-231) regrew after terminating sunitinib administration. However, this effect was not observed in mice engrafted with a non-TNBC tumor cell line. Tumor metastases in sunitinib-treated TA2 mice was accelerated, and the survival of these mice decreased when sunitinib was withdrawn. VM was the major component of the microcirculation in sunitinib-treated mice with TNBC tumors, and the population of CD133+ cells increased in hypoxic areas. Hypoxia also induced MDA-MB-231 cells to express Twist1, and CD133(+) cells present in the MDA-MB-231 cell population induced VM after reoxygenation. Moreover, hypoxia did not induce MDA-MB-231 cells transfected with an sh-Twist1 siRNA cell to form VM and generate CD133(+) cells. Conversely, hypoxia induced MCF-7 cells transfected with Twist to form VM and generate CD133+ cells. CONCLUSIONS: Sunitinib induced hypoxia in TNBCs, and Twist1 expression induced by hypoxia accelerated VM by increasing population of CD133(+) cells. VM was responsible for the regrowth of TNBCs sunitinib administration was terminated.

An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy.

Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR-dCas9 in targeting AURKA or KDM1A and improving disease-specific prognosis and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA-triggered CRISPR-dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.

Interplay of IGF1R and estrogen signaling regulates hematopoietic stem and progenitor cells.

Tissue stem cells often exhibit developmental stage-specific and sexually dimorphic properties, but the underlying mechanism remains largely elusive. By characterizing IGF1R signaling in hematopoietic cells, here we report that its disruption exerts sex-specific effects in adult hematopoietic stem and progenitor cells (HSPCs). Loss of IGF1R decreases the HSPC population in females but not in males, in part due to a reduction in HSPC proliferation induced by estrogen. In addition, the adult female microenvironment enhances engraftment of wild-type but not Igf1r-null HSPCs. In contrast, during gestation, when both female and male fetuses are exposed to placental estrogens, loss of IGF1R reduces the numbers of their fetal liver HSPCs regardless of sex. Collectively, these data support the interplay of IGF1R and estrogen pathways in HSPCs and suggest that the proliferation-promoting effect of estrogen on HSPCs is in part mediated via IGF1R signaling.

HER2/neu expression correlates with vasculogenic mimicry in invasive breast carcinoma.

Vasculogenic mimicry (VM) refers to the condition in which tumour cells mimic endothelial cells to form extracellular matrix-rich tubular channels. VM is more extensive in more aggressive tumours. The human epidermal growth factor receptor 2 (HER2) gene is amplified in 20-30% of human breast cancers and has been implicated in mediating aggressive tumour growth and metastasis. However, thus far, there have been no data on the role of HER2 in VM formation. Immunohistochemical and histochemical double-staining methods were performed to display VM in breast cancer specimens. Transfection in MCF7 cells was performed and clones were selected by G418. The three-dimensional Matrigel culture was used to evaluate VM formation in the breast cancer cell line. According to statistical analysis, VM was related to the presence of a positive nodal status and advanced clinical stage. The positive rate of VM increased with increased HER2 expression. In addition, cases with HER2 3+ expression showed significantly greater VM channel count than those in other cases. The exogenous HER2 overexpression in MCF-7 cells induced vessel-like VM structures on the Matrigel and increased the VM mediator vascular endothelial (VE) cadherin. Our data provide evidence for a clinically relevant association between HER2 and VM in human invasive breast cancer. HER2 overexpression possibly induces VM through the up-regulation of VE cadherin. Understanding the key molecular events may provide therapeutic intervention strategies for HER2+ breast cancer.

Slug promoted vasculogenic mimicry in hepatocellular carcinoma.

Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. Epithelial-mesenchymal transition (EMT) regulator slug have been implicated in the tumour invasion and metastasis of human hepatocellular carcinoma (HCC). However, the relationship between slug and VM formation is not clear. In the study, we demonstrated that slug expression was associated with EMT and cancer stem cell (CSCs) phenotype in HCC patients. Importantly, slug showed statistically correlation with VM formation. We consistently demonstrated that an overexpression of slug in HCC cells significantly increased CSCs subpopulation that was obvious by the increased clone forming efficiency in soft agar and by flowcytometry analysis. Meantime, the VM formation and VM mediator overexpression were also induced by slug induction. Finally, slug overexpression lead to the maintenance of CSCs phenotype and VM formation was demonstrated in vivo. Therefore, the results of this study indicate that slug induced the increase and maintenance of CSCs subpopulation and contributed to VM formation eventually. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis.

Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma.

BACKGROUND: The aim of this study was to investigate the clinical significances and prognostic value of CD133 and CD44 (markers of cancer stem-like cells, CSCs), and vasculogenic mimicry (VM) in renal cell carcinoma (RCC). METHODS: Immunohistochemistry was performed to detect CD133 and CD44 expression and VM in 110 RCC patients proven to exhibit de novo metastases after radical nephrectomy. RESULTS: In RCC, positive rates of 27.3%, 20.9%, and 21.8% were obtained for CD44, CD133, and VM, respectively. CD44 was significantly associated with tumor size, grade, stage, and histological type. CD44 expression may serve as a predictor of the number of metastases sites in RCC. CD133 expression correlated with tumor grade, stage, histological type, and tumor location. VM was positively associated with tumor grade and stage. Microvessel density (MVD) positively corresponded to tumor size, grade, and stage. CD133 expression was not associated with MVD, but significantly correlated with VM. CD44 expression correlated marginally with VM, but was found to have a significantly association with MVD. A close relationship between CSCs, MVD, and VM was established. The overall survival times of patients with CD133-high positive, CD44-high positive, VM-positive, and MVD <43 were lower than that of the patients with low positive, negative, and MVD ≥43. Tumor grade and presence of VM were independent prognostic factors of RCC. CONCLUSIONS: Findings show that higher CSCs and VM was correlated with more aggressive clinicopathologic. VM was an independent unfavorable prognostic factor. The authors consistently observed that CSCs may be related to angiogenesis and vasculogenic mimicry.

TET3 Mediates 5hmC Level and Promotes Tumorigenesis by Activating AMPK Pathway in Papillary Thyroid Cancer.

Thyroid cancer is the most common endocrine malignant tumor. The accurate risk stratification and prognosis assessment is particularly important for patients with thyroid cancer, which can reduce the tumor recurrence rate, morbidity, and mortality effectively. DNA methylation is one of the most widely studied epigenetic modifications. Many studies have shown that 5hmC-mediated demethylation played an important role in tumors. The hydroxylation of 5mC is catalyzed by ten-eleven translocation dioxygenase (TET). In this study, we first found that the abnormal expression of 5hmC was closely related to microcarcinoma, multifocal, extraglandular invasion and lymph node metastasis of thyroid carcinoma. Then, we identified TET3 was differentially expressed in thyroid cancers and normal tissues from the TET family. TET3 can promote the proliferation, migration, and invasion of thyroid cancer. TET3-mediated 5hmC can regulate the transcription of AMPK pathway-related genes to activate the AMPK pathway and autophagy and therefore promote PTC proliferation. These findings provide a preclinical rationale for the design of novel therapeutic strategies for this target to improve the clinical outcome of patients with PTC.

Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma.

CpG island methylator phenotype (CIMP), characterized by the concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have explored the role of CIMP in papillary thyroid carcinomas (PTCs). Here, in genome-wide DNA methylation analysis of 350 primary PTCs from the Cancer Genome Atlas database that were assessed using the Illumina HumanMethylation450K platform, our study helps to identify two subtypes displayed markedly distinct DNA methylation levels, termed CIMP (high levels of DNA methylation) and nCIMP subgroup (low levels of DNA methylation). Interestingly, PTCs with CIMP tend to have a higher degree of malignancy, since this subtype was tightly associated with older age, advanced pathological stage, and lymph node metastasis (all P < 0.05). Differential methylation analysis showed a broad methylation gain in CIMP and subsequent generalized gene set testing analysis based on the significantly methylated probes in CIMP showed remarkable enrichment in epithelial mesenchymal transition and angiogenesis hallmark pathways, confirming that the CIMP phenotype may promote the tumor progression from another perspective. Analysis of tumor microenvironment showed that CIMP PTCs are in an immune-depletion status, which may affect the effectiveness of immunotherapy. Genetically, the significantly higher tumor mutation burden and copy number alteration both at the genome and focal level confirmed the genomic heterogeneity and chromosomal instability of CIMP. tumor Corresponding to the above findings, PTC patients with CIMP showed remarkable poor clinical outcome as compared to nCIMP regarding overall survival and progression-free survival. More importantly, CIMP was associated with worse survival independent of known prognostic factors.

Ultrasound features of medullary thyroid cancer as predictors of biological behavior.

BACKGROUND: Medullary thyroid cancer (MTC) has more aggressive behavior and poor prognosis. Ultrasound (US) has facilitated the qualitative diagnosis of thyroid nodules, however, some MTC may be diagnosed as a benign nodule on ultrasound because ultrasound features of malignancy are lacking. The aim of the study was to investigate the association between ultrasound features and biological behavior of MTC. METHODS: Ultrasound findings and medical records of patients with MTC between Jan 2015 to Jun 2017 were retrospectively reviewed at Tianjin Medical University Cancer Institute and Hospital. MTC were categorized using modified TI-RADS classification, then were classified as "malignant" (m-MTC) or "US-low-suspicious" (l-MTC). We compared the biological behavior between the two groups, and further analyzed the risk factors for the recurrence. RESULTS: A total of 78 patients were enrolled, of which 55 m-MTC (70.5%) and 23 l-MTC (29.5%) were identified. The N staging of the m-MTC was significantly higher than that of l-MTC(P = 0.000). The preoperative serum Ct level in m-MTC were significantly higher than that of l-MTC(P = 0.035). Biochemical cure were more frequent in l-MTC than that of m-MTC (P = 0.002). Disease recurrence rates were 19.7% (14 of 71). Disease recurrence was more frequent in m-MTC than that of l-MTC (P = 0.013). Disease recurrence was positively associated with extrathyroid extension (P = 0.047), N staging (P = 0.003), preoperative serum Ct level (P = 0.009) and negatively associated with biochemical cure(P = 0.000). In multivariable Cox regression analysis, extrathyroid extension and biochemical cure were independent risk factors for recurrence of MTC. CONCLUSIONS: L-MTC has a more indolent character than m-MTC. The extrathyroid extension and biochemical cure were independent risk factors for recurrence of MTC.

A CRISPR-Cas9-Based Near-Infrared Upconversion-Activated DNA Methylation Editing System.

DNA methylation is a kind of a crucial epigenetic marker orchestrating gene expression, molecular function, and cellular phenotype. However, manipulating the methylation status of specific genes remains challenging. Here, a clustered regularly interspaced palindromic repeats-Cas9-based near-infrared upconversion-activated DNA methylation editing system (CNAMS) was designed for the optogenetic editing of DNA methylation. The fusion proteins of photosensitive CRY2PHR, the catalytic domain of DNMT3A or TET1, and the fusion proteins for CIBN and catalytically inactive Cas9 (dCas9) were engineered. The CNAMS could control DNA methylation editing in response to blue light, thus allowing methylation editing in a spatiotemporal manner. Furthermore, after combination with upconversion nanoparticles, the spectral sensitivity of DNA methylation editing was extended from the blue light to near-infrared (NIR) light, providing the possibility for remote DNA methylation editing. These results demonstrated a meaningful step forward toward realizing the specific editing of DNA methylation, suggesting the wide utility of our CNAMS for functional studies on epigenetic regulation and potential therapeutic strategies for related diseases.

High expression of NUCB2 promotes papillary thyroid cancer cells proliferation and invasion.

BACKGROUND: NUCB2, a novel multifunctional protein containing several functional domains, was newly found to play important roles in many cancers, but its role in papillary thyroid cancer (PTC) is not well investigated. Therefore, our study was performed to explore the functions of NUCB2 in PTC. METHODS: NUCB2 protein level was analyzed by immunohistochemistry. Data analyses were made by performing chi-squared test. Quantitative reverse-transcription PCR, Western blot, colony formation, MTT, and transwell invasion assays were performed to test the expression levels and functions of NUCB2 in PTC. RESULTS: In PTC tissues, NUCB2 protein expression level was positively correlated with extrathyroidal extension, TNM stage, and tumor size of PTC patients. In vitro experiments demonstrated that knockdown of NUCB2 using specific shRNA for NUCB2 significantly impaired cell proliferation and invasion of PTC cell lines. In vivo, silencing of NUCB2 inhibited the growth of tumors in mice. CONCLUSION: These results suggested a novel function of NUCB2 in the process of proliferation and invasion in PTC. NUCB2 may be considered a potent prognostic factor in PTC.

Risk factors for cervical lymph node metastasis in papillary thyroid microcarcinoma: a study of 1,587 patients.

OBJECTIVE: The purposes of this study were to identify risk factors for cervical lymph node metastasis and to examine the association between BRAF V600E status and clinical features in papillary thyroid microcarcinoma (PTMC). METHODS: A total of 1,587 patients with PTMC, treated in Tianjin Medical University Cancer Institute and Hospital from January 2011 to March 2013, underwent retrospective analysis. We reviewed and analyzed factors including clinical results, pathology records, ultrasound results, and BRAF V600E status. RESULTS: Multivariate logistic regression analyses demonstrated that gender (male) [odds ratio (OR) = 1.845, P = 0.000], age (< 45 years)(OR = 1.606,P = 0.000), tumor size (> 6 mm) (OR = 2.137,P = 0.000), bilateralism (OR = 2.011, P = 0.000) and extrathyroidal extension (OR = 1.555, P = 0.001) served as independent predictors of central lymph node metastasis (CLNM). Moreover, CLNM (OR = 29.354, P = 0.000) served as an independent predictor of lateral lymph node metastasis (LLNM). Among patients with a solitary primary tumor, those with tumor location in the lower third of the thyroid lobe or the isthmus were more likely to experience CLNM (P < 0.05). Univariate analyses indicated that CLNM, LLNM, extrathyroidal extension, and multifocality were not significantly associated with BRAF V600E mutation. CONCLUSIONS: The present study suggested that prophylactic neck dissection of the central compartment should be considered in patients with PTMC, particularly in men with tumor size greater than 6 mm, age less than 45 years, extrathyroidal extension, and tumor bilaterality. Among patients with PTMC, BRAF V600E mutation is not significantly associated with prognostic factors. For a better understanding of surgical management of PTMC and the risk factors, we recommend multicenter research and long-term follow-up.

Integrated microRNA-mRNA analyses of distinct expression profiles in follicular thyroid tumors.

MicroRNAs (miRNAs/miRs) are small non-coding RNAs identified in plants, animals and certain viruses; they function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs also serve an important role in the pathogenesis, diagnosis and treatment of tumors. However, few studies have investigated the role of miRNAs in thyroid tumors. In the present study, the expression of miRNA and mRNA was compared between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FA) samples, and then miRNA-mRNA regulatory network analysis was performed. Microarray datasets (GSE29315 and GSE62054) were downloaded from the Gene Expression Omnibus, and profiling data were processed with R software. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were determined, and Gene Ontology enrichment analysis was subsequently performed for DEGs using the Database for Annotation, Visualization and Integrated Discovery. The target genes of the DEMs were identified with miRWalk, miRecords and TarMir databases. Network analysis of the DEMs and DEMs-targeted DEGs was performed using Cytoscape software. In GSE62054, 23 downregulated and 9 upregulated miRNAs were identified. In GSE29315, 42 downregulated and 44 upregulated mRNAs were identified. A total of 36 miRNA-gene pairs were also identified. Network analysis indicated a co-regulatory association between miR-296-5p, miR-10a, miR-139-5p, miR-452, miR-493, miR-7, miR-137, miR-144, miR-145 and corresponding targeted mRNAs, including TNF receptor superfamily member 11b, benzodiazepine receptor (peripheral) -associated protein 1, and transforming growth factor ß receptor 2. These results suggest that miRNA-mRNAs networks serve an important role in the pathogenesis, diagnosis and treatment of FTC and FA.

Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress.

Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.

Cucurbitacin B synergistically enhances the apoptosis-inducing effect of arsenic trioxide by inhibiting STAT3 phosphorylation in lymphoma Ramos cells.

Arsenic trioxide (ATO) is a classic apoptosis-inducing agent used to treat acute promyelocytic leukemia. However, the therapeutic effect of ATO is limited in lymphoma, which resists apoptosis possibly due to inappropriate activation of STAT3. Therefore, combination of ATO and STAT3 inhibitor may be a potential strategy to treat lymphoma. Dramatically, Cucurbitacin B (CuB), an effective component of the dichloromethane extraction from Trichosanthes kirilowii Maxim, synergistically eliminated the apoptosis resistance of Burkitt's lymphoma Ramos cells to ATO by inhibiting the phosphorylation of STAT3, followed in turn by downregulation of Bcl-2 and upregulation of Bax. Furthermore, CuB and ATO in combination have no pro-apoptotic effect on normal lymphatic cells, indicating the absence of toxicity to hematological cells. This synergistic effect was further confirmed in nude murine lymphoma model, which exhibited significant apoptosis induction and tumor growth inhibition. Collectively, CuB synergistically enhances the apoptosis-inducing effect of ATO by inhibiting STAT3 phosphorylation in Ramos cells.

miR-24 promotes the proliferation, migration and invasion in human tongue squamous cell carcinoma by targeting FBXW7.

Recent studies suggest that aberrant expression of miR-24 is linked to various human cancers, including tongue squamous cell carcinoma (TSCC). F-box and WD-40 domain protein 7 (FBXW7), a tumor-suppressor gene, is responsible for the degradation of several proto-oncogenes. However, the function and mechanism of miR-24 and FBXW7 in TSCC remains unclear. In the present study, we found that miR-24 was increased in TSCC tissues and cell lines, and that upregulation of miR-24 was associated with advanced clinical stage and a shorter overall survival of TSCC patients. Inhibition of miR-24 significantly suppressed the proliferation, migration and invasion of TSCC cells in vitro. Furthermore, miR-24 repressed FBXW7 expression by directly binding to the 3-untranslated region of FBXW7. Moreover, the suppression of FBXW7 increased the proliferation, migration and invasion of TSCC cells, and the restoration of FBXW7 substantially attenuated the oncogenic effects of miR-24. In conclusion, our results demonstrated that upregulation of miR-24 was associated with tumor progression and poor prognosis in TSCC patients, and that overexpression of miR-24 was correlated with the proliferation, migration and invasion of TSCC cells in vitro, at least partially through regulation of its functional target FBXW7. Thus, miR-24 may serve as a novel potential biomarker for the prognosis of TSCC patients.

MicroRNA-24 induces cisplatin resistance by targeting PTEN in human tongue squamous cell carcinoma.

BACKGROUND: miR-24 is one of the most significantly up-regulated miRNAs in tongue squamous cell carcinoma (TSCC). PTEN plays an important role in the cell survival and cisplatin resistance of multiple cancers. However, it remains unclear what role does function and mechanism of miR-24 and PTEN play in TSCC. METHODOLOGY/PRINCIPAL FINDINGS: In this study, miR-24 expression was detected in 79 cases of paired TSCC and normal tissues and 8 TSCC cell lines by real-time PCR and the relevance between miR-24 expression and clinicopathological parameters were analyzed. Further, we demonstrated that deregulation of miR-24 was found to associate with high grade and late stage tumor. In addition, miR-24 induces cell survival and cisplatin resistance through targeting 3'-UTR region of the PTEN, which leads to downregulation of PTEN protein and activation of Akt pro-survival pathway. CONCLUSIONS/SIGNIFICANCE: In conclusion, our results demonstrated that deregulation of miR-24 is a recurrent event in human tongue squamous cell carcinoma and associate with tumor progression and that miR-24 induces cell survival and cisplatin resistance primarily through targeting PTEN/Akt pathway. Thus, miR-24 could be important targets for intervention of this malignancy.

Nodule and eminence on frenulum labii superioris: diagnostic markers for metastatic colorectal cancer.

OBJECTIVE: To determine whether the nodule and eminence on the frenulum labii superioris, location of Yinjiao (DU28) according to the meridian theory, could be used to prognosticate the recurrence of patients with colorectal cancer. METHODS: The data of 101 patients with colorectal cancer in Tianjin Medical University Cancer Institute and Hospital from May 2011 to November 2011 was analyzed. The photos of all patients' frenulum labii superioris were taken. Nodule and eminence on frenulum labii superioris were the positive standard. Biopsy and pathological testing for the nodule were carried out on one patient with large nodule on frenulum labii superioris. RESULTS: Patients with positive frenulum labii superioris had a higher risk of recurrence and/or metastasis than patients with negative frenulum labii superioris. There were no significant differences in diagnosis of recurrence and/or metastasis between the status of frenulum labii superioris and the traditional diagnostic criteria (P =0.238). The Kappa was 0.606 (P <0.001). The sensitivity was 76.0% and the specificity was 85.4%. The pathological report demonstrated that the nodule on frenulum labii superioris was mucosal excrescence with normal structure. CONCLUSION: Nodule and eminence on frenulum labii superioris are potential diagnostic markers for metastatic colorectal cancer.