CCL18 promotes the metastasis of squamous cell carcinoma of the head and neck through MTDH-NF-κB signalling pathway.

Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C-C motif) ligand 18 (CCL18), derived from tumour-associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial-mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18-induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF-κB signalling pathway was involved in the MTDH knock-down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment-naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH-NF-κB signalling pathway.

Analysis of transcriptional factors and regulation networks in laryngeal squamous cell carcinoma patients with lymph node metastasis.

The present study was to identify and quantitate differentially expressed proteins in laryngeal squamous cell carcinoma (LSCC) tissues with or without lymph node metastasis and to explore transcriptional factors and regulation networks associated with the process. Tissue specimens were taken from 20 patients with LSCC, including 10 cases of LSCC without metastasis LSCC (N0) and 10 cases of LSCC with metastasis LSCC (Nx). Among the 643 unique proteins identified by using iTRAQ labeling and quantitative proteomic technology, 389 proteins showed an abundance change in LSCC (Nx) as compared to LSCC (N0). Cytoskeleton remodeling, cell adhesion, and immune response activation were found to be the main processes in LSCC metastasis. The construction of transcription regulation networks identified key transcription regulators for lymph node metastasis of LSCC, including Sp1, c-myc, and p53, which may affect LSCC metastasis through the epithelial-mesenchymal transition. Furthermore, our results suggest that ubiquitination may be a critical factor in the networks. The present study provides insights into transcriptional factors and regulation networks involved in LSCC metastasis, which may lead to new strategies for treatment of LSCC metastasis.

MRI features of different types of sinonasan rhabdomyosarcomas: a series of eleven cases.

OBJECTIVE: To retrospectively analyze magnetic resonance imaging (MRI) features of various pathological subtypes of sinonasal rhabdomyosarcoma (RMS) and explore correlations between imaging features and pathological subtypes. METHODS: In total, 11 cases with embryonal, alveolar or pleomorphic sinonasal RMSs, confirmed by surgical pathology, were selected. Their characteristics and distinctive imaging features were analysed, and the correlation between pathology and imaging features was explored. RESULTS: Bone destruction was observed in all 11 cases with RMS. Expansive growth was predominant in three alveolar and three embryonal RMS cases, and creeping growth was predominant in two alveolar, two embryonal and one pleomorphic RMS cases. Signs of residual mucosa were observed in all 11 cases, and 10 cases showed involvement of multiple sinus cavities and orbital cavities. All cases exhibited mild-to-intermediate enhancement. CONCLUSION: Sinonasal RMSs have the following characteristic MRI features: ethmoid sinuses and middle nasal conchae are the prevalent sites; lesions are mainly of mild enhancement; tumours exhibit signs of residual mucosa, mild-to-intermediate enhancement and frequent orbital involvement; bone invasion and bone destruction are frequently observed; and haematogenous metastasis is not as common as lymphatic metastasis. RMSs of various pathological subtypes were not significantly distinct by imaging.

Six-gene signature for predicting survival in patients with head and neck squamous cell carcinoma.

The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. High-throughput sequencing data have laid a solid foundation for identifying genes related to cancer prognosis, but a gene marker is needed to predict clinical outcomes in HNSCC. In our study, we downloaded RNA Seq, single nucleotide polymorphism, copy number variation, and clinical follow-up data from TCGA. The samples were randomly divided into training and test. In the training set, we screened genes and used random forests for feature selection. Gene-related prognostic models were established and validated in a test set and GEO verification set. Six genes (PEX11A, NLRP2, SERPINE1, UPK, CTTN, D2HGDH) were ultimately obtained through random forest feature selection. Cox regression analysis confirmed the 6-gene signature is an independent prognostic factor in HNSCC patients. This signature effectively stratified samples in the training, test, and external verification sets (P < 0.01). The 5-year survival AUC in the training and verification sets was greater than 0.74. Thus, we have constructed a 6-gene signature as a new prognostic marker for predicting survival of HNSCC patients.

A Prognostic 5-lncRNA Expression Signature for Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common malignant cancer that accounts for 5-10% of all cancers. This study aimed to identify essential genes associated with the prognosis of HNSCC and construct a powerful prognostic model for the risk assessment of HNSCC. RNAseq expression profile data for the patients with HNSCC were obtained from the TCGA database (GEO). A total of 500 samples with full clinical following-up were randomly divided into a training set and a validation set. The training set was used to screen for differentially expressed lncRNAs. Single-factor survival analysis was performed to obtain lncRNAs that associated with prognosis. A robust likelihood-based survival model was constructed to identify the lncRNAs that are essential for the prognosis of HNSCC. A co-expression network between genes and lncRNAs was also constructed to identify lncRNAs co-expressed with genes to serve as the final signature lncRNAs for prognosis. Finally, the prognostic effect of the signature lncRNAs was tested by multi-factor survival analysis and a scoring model for the prognosis of HNSCC was constructed. Moreover, the results of the validation set and the relative expression levels of the signature lncRNAs in the tumour and the adjacent tissue were consistent with the results of the training set. The 5 lncRNAs were distributed among 3 expression modules. Further KEGG pathway enrichment analysis showed that these 3 co-expressed modules participate in different pathways, and many of these pathways are associated with the development and progression of disease. Therefore, we proposed that the 5 validated lncRNAs can be used to predict the prognosis of HNSCC patients and can be applied in postoperative treatment and follow-up.

MiR-98 inhibits malignant progression via targeting MTDH in squamous cell carcinoma of the head and neck.

PURPOSE: MicroRNAs function through regulating specific target mRNA expression and then participate in the development and progression of diverse human cancers. MiR-98 shows aberrant expression and dysfunction in tumors. However, its clinical significance and exact role in squamous cell carcinoma of the head and neck (SCCHN) remain elusive. METHODS: MiR-98 expression was examined by qRT-PCR and correlated with clinicopathological variables and prognosis in SCCHN patients. Effects of miR-98 on epithelial-mesenchymal transition (EMT) and the malignant phenotypes of SCCHN were studied. Finally, the role of target gene metadherin (MTDH) in miR-98 mediated effects were assayed. RESULTS: Our results demonstrated that miR-98, as an endogenous inhibitor of MTDH via directly binding to its 3'-untranslated region (UTR) region, decreased significantly in SCCHN tissues. Decreased miR-98 expression was negatively correlated with T classification, clinical stage, lymph node metastasis and a shorter survival status in SCCHN patients. Loss-of-function and gain-of-function analyses confirmed that miR-98 inhibited cell proliferation, migration and invasion of SCCHN cells in vitro. Moreover, miR-98 repression led to increased MTDH expression and induced EMT alteration. Importantly, ectopic expression of MTDH partially reversed the effects caused by miR-98 overexpression. CONCLUSIONS: Our study identifies that miR-98 serves as a suppressor in SCCHN progression via targeting oncogene MTDH.

Elevated expression of Derlin-1 associates with unfavorable survival time of squamous cell carcinoma of the head and neck and promotes its malignance.

Derlin-1 is over-expressed to function as an oncoprotein in breast, lung and colon cancers. However, the implications of Derlin-1 involved in squamous cell carcinoma of the head and neck (SCCHN) remain unknown. This study aims to investigate the effects of Derlin-1 expression on SCCHN tissues and cells. The potential mechanism of Derlin-1 regulating SCCHN cell proliferation, apoptosis and metastasis was also indicated in this work. Western blot and immunohistochemistry (IHC) assays showed that Derlin-1 was over-expressed in 114 SCCHN samples and five SCCHN cell lines. We found that the expression of Derlin-1 was positively associated with lymph node metastasis, clinical stage and recurrence in our SCCHN patients' samples. Survival analysis indicated that high expression of Derlin-1 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Knock down expression of Derlin-1 in SCCHN cell lines was found to inhibit cell proliferation, metastasis and promote cell apoptosis. Further experiments showed that signals of PI3K/Akt, p53 and Smad2/3 may involve in these processes. In all, Derlin-1 might be a novel prognostic marker of SCCHN patients and plays an oncogenic role in SCCHN cell progression.

An individual drug-therapy and genetic testing report of temporal bone verrucous carcinoma.

OBJECTIVE: To investigate the pathology and pathogenesis of and treatment methods for temporal bone verrucous carcinoma. MATERIALS AND METHODS: A single-patient report of verrucous carcinoma on the left external auditory canal is presented and analyzed along with all cases of temporal bone verrucous carcinoma that have been documented in the English literature. RESULTS: Most of the patients with verrucous carcinoma of the temporal bone have histories of surgery, trauma, or infection, and verrucous carcinomas are sensitive to antimicrotubule chemotherapeutic medicines. Adjuvant radiation therapy is not effective, but surgical treatment might be relatively more effective. CONCLUSION: Temporal bone verrucous carcinoma has a poor prognosis; therefore, the preferred treatment is surgical resection facilitated with antimicrotubule chemotherapeutic treatment. Adjuvant radiation therapy is not a preferred treatment for temporal bone verrucous carcinoma.

Increased expression of Rab coupling protein in squamous cell carcinoma of the head and neck and its clinical significance.

The role of Rab coupling protein (RCP) has not been previously investigated in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to explore RCP protein expression and its clinicopathological significance in SCCHN. RCP protein expression in 95 SCCHN samples, 18 vocal nodule epithelia and 16 leukoplakia epithelia samples was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Our data indicated that vocal nodule epithelia, leukoplakia epithelia and SCCHN showed a gradual increase in the expression of RCP protein. RCP overexpression was significantly associated with T classification, clinical staging, lymph node metastasis and recurrence. Survival analysis revealed that a high RCP expression was significantly correlated with shorter overall survival and disease-free survival. In conclusion, RCP protein may contribute to the malignant progression of SCCHN, and serves as a novel prognostic marker in patients with SCCHN.

[EGCG regulates TGF-ß1-induced epithelial mesenchymal transition in squamous cell carcinoma of head and neck].

OBJECTIVE: To study the effect and molecular mechanism of epigallocatechin-3-gallate (EGCG) on epithelial-mesenchymal transition (EMT) in vitro induced by human recombinant TGF-ß1 protein in squamous cell carcinoma of the head and neck. METHODS: EMT morphological changes of Tu686 cells were observed after sequential treatment of 5 ng/ml TGF-ß1 and 20 µmol/L EGCG. Tu686 cells were collected after the treatment of 5 ng/ml TGF-ß1 for 24 h and EGCG with different concentrations (0, 10, 20, 30 µmol/L) for another 24 h or 20 µmol/L EGCG treatment for different time phase (6, 12, 24 h). Then RT-PCR and Western-blot were applied to detect mRNA and protein expression level of epithelial cell marker E-cadherin, mesenchymal cell marker Vimentin and Smad7, an inhibit molecule of TGF-ß1 mediated pathway in Tu686 cells. RESULTS: TGF-ß1 successfully induced characterized EMT morphological and molecular changes in Tu686 cells, in which expression of E-cadherin decreased, Vimentin increased and Smad7 declined. However, EGCG could reverse the TGF-ß1 mediated process of EMT by downregulating the expression of Vimentin and upregulating the expression of E-cadherin and Smad7. CONCLUSION: EGCG significantly inhibits TGF-ß1-mediated EMT inTu686 cell lines of SCCHN, which maybe associated with the upregulated-expression of Smad7, an inhibitor in TGF-ß1 signaling pathway.

Bone morphogenetic protein-4-induced epithelial-mesenchymal transition and invasiveness through Smad1-mediated signal pathway in squamous cell carcinoma of the head and neck.

BACKGROUND AND AIMS: Bone morphogenetic proteins (BMPs) have recently been shown to be involved in the genesis and progression of a wide variety of carcinomas. The present study was undertaken to estimate the effect of BMP-4 on squamous cell carcinoma of the head and neck (SCCHN) in tissue and cell levels. METHODS: In this study, immunohistochemistry, Western blotting and RT-PCR were utilized to detect the expression of BMP-4, Smad1 and phosphorylated Smad1 in SCCHN tissues or SCCHN cell lines. Those three proteins in tissues were further correlated with prognosis of SCCHN by Kaplan-Meier analysis. The epithelial-mesenchymal transition (EMT)-associated changes in SCCHN cells were detected after stimulation by human BMP-4 recombinant protein and knockdown of Smad1 gene. Meanwhile, the effect on invasiveness and migration was evaluated by invasion and scratch assays, respectively. RESULTS: BMP-4 and p-Smad1 protein were overexpressed in SCCHN tissues with cervical lymph node metastasis, which was significantly higher than those without metastasis. The expression of BMP-4 and p-Smad1 protein was negatively correlated with the prognosis of SCCHN. BMP-4 promoted the invasiveness and migration through EMT, which was demonstrated by morphological alterations, loss of E-cadherin, increase of vimentin and activation of the Smad1 signal pathway. Knockdown of Smad1 expression suppressed BMP-4 induced EMT in both cell lines and weakened the invasiveness and migration of Tu686 and Tu212 in vitro. CONCLUSIONS: Our results demonstrate that BMP-4 protein may contribute to the malignant metastasis of SCCHN, which presents as a novel prognostic marker and a potential therapeutic target for patients with SCCHN.