Expression and Prognostic Significance of Cadherin 4 (CDH4) in Renal Cell Carcinoma.

BACKGROUND Aberrant expression of cadherin family members and their possible biological function have been widely studied in renal cell carcinoma (RCC). However, the expression of cadherin 4 (CDH4) and its value in RCC diagnosis and prognosis remains elusive. MATERIAL AND METHODS The TCGA database was used to analyze the expression of CDH4 and its clinical parameters and prognosis in 891 RCC patients. In addition, real-time PCR was used to verify the transcription of CDH4 in renal clear cell carcinoma tissue, and the distribution of protein was observed by immunohistochemical staining. RESULTS We found that the mRNA level of CDH4 was elevated in primary RCC in contrast with normal kidney samples using bioinformatics analysis based on the TCGA database. Among the 3 main subtypes of RCC, transcriptional CDH4 was significantly increased in KIRC and KIRP, while it was downregulated in KICH. Interestingly, CDH4 mRNA gradually decreased with the progression of KIRC and KIRP. The transcription of CDH4 in the primary tumor of KIRP patients at T3-T4 stages and KIRC patients with lymph node and distant metastasis were decreased significantly. Overall survival (OS) showed that KIRC and KICH patients with lower expression of CDH4 had worse outcomes. CONCLUSIONS The transcriptional level of CDH4 may serve as an effective diagnostic and prognostic biomarker for RCC patients.

Knockdown Rab11-FIP2 inhibits migration and invasion of nasopharyngeal carcinoma via suppressing Rho GTPase signaling.

Rab11 family interacting protein 2 (Rab11-FIP2) is a conserved protein and effector molecule for the small GTPase Rab11. By interacting with Rab11 and MYO5B, Rab11-FIP2 regulates endosome trafficking of plasma membrane proteins, promoting cellular motility. The endosomal trafficking system in nasopharyngeal carcinoma (NPC) remains unclear. Here, an outlier analysis using the Oncomine database suggested that Rab11-FIP2 but not Rab11 and MYO5B was overexpressed in NPC. We confirmed that the transcription of Rab11-FIP2 was upregulated in NPC cell lines and primary tumor tissues as compared with a normal nasopharyngeal epithelial cell line and normal nasopharynx tissues. We further confirmed the elevated protein expression level of Rab11-FIP2 in NPC biopsies. Instead of regulating the epithelial-mesenchymal transition or Akt signaling pathway, knockdown of Rab11-FIP2 inhibited the migration and invasion ability of NPC cell lines by decreasing the expression of Rac and Cdc42. In summary, Rab11-FIP2 could be an oncogene in NPC, mainly contributing to metastatic capacity by activating Rho GTPase signaling.

Inactivation of 3-hydroxybutyrate dehydrogenase type 2 promotes proliferation and metastasis of nasopharyngeal carcinoma by iron retention.

BACKGROUND: 3-Hydroxybutyrate dehydrogenase type 2 (BDH2) is known to catalyse a rate-limiting step in the biogenesis of the mammalian siderophore and regulate intracellular iron metabolism. Here we aim to explore the expression and possible function of BDH2 in nasopharyngeal carcinoma (NPC). METHODS: The transcription and protein expression of BDH2 in NPC were determined by both real-time RT-PCR and immunohistochemistry staining assays. Cell proliferation, migration and invasion were evaluated by MTT assay, wound-healing assay and Transwell assay, respectively. The profile of genes regulated by restoring BDH2 expression in NPC cells was analysed by cDNA microarray. The level of iron in NPC cells was detected by iron colorimetric assay. RESULTS: The expression of BDH2 was significantly downregulated in NPC. Ectopic expression of BDH2 inhibited NPC cell proliferation and colony formation. Meanwhile, BDH2 suppressed the migration and invasion of NPC cells by reversing the epithelial-mesenchymal transition (EMT). In addition, a higher level of BDH2 decreased the growth and metastasis of NPC cells via reducing intracellular iron level. CONCLUSIONS: Our findings suggest that BDH2 may be a candidate tumour-suppressor gene in NPC. Decreasing intracellular iron could be an effective therapeutic approach for NPC.

An Inflammation-Immunity Classifier of 11 Chemokines for Prediction of Overall Survival in Head and Neck Squamous Cell Carcinoma.

BACKGROUND Chemokines are important in inflammation, immunity, tumor progression, and metastasis. The purpose of this research was to find an integrated-RNA signature of chemokine family genes to predict the survival prognosis in head and neck squamous carcinoma (HNSC) patients. MATERIAL AND METHODS Relevant data of 504 HNSC patients were extracted from The Cancer Genome Atlas (TCGA) database. Through analyzing RNA sequencing data, the univariate Cox model was used to identify chemokine family genes associated with survival and then to develop a multiple-RNA signature in the training set. The prediction value of this multiple-RNA signature was further verified in the validation and entire sets. The receiver operating characteristic curves were used to assess the predictive value of this multiple-RNA signature. RESULTS Eleven chemokines were included in this prognostic signature. Based on this 11-chemokine signature, we further categorized patients as high or low risk. Compared with low-risk patients, high-risk patients had shorter overall survival (OS) time in the training set [hazard ratio (HR)=3.497, 95% confidence interval (CI)=2.142-5.711, p<0.001], validation set (HR=3.575, 95% CI=1.988-6.390, p<0.001), and entire set (HR=3.416, 95% CI=2.363-4.939, p<0.001). This 11-chemokine signature was an independent prognostic factor for OS in these datasets (p<0.05). The AUC values for predicting overall survival within 48 months in the training, validation, and entire sets were 0.71, 0.69, and 0.69, respectively. CONCLUSIONS This 11-chemokine signature could serve as a reliable prognostic tool for HNSC patients and might be useful to guide individualized treatment or even gene target therapy for high-risk patients.

Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway.

Purpose: Caffeic acid phenethyl ester (CAPE) is the main polyphenol extracted from honeybee propolis, which inhibits the growth of several kinds of tumor. This study aimed to assess the inhibitory effect of CAPE in nasopharyngeal carcinoma (NPC), evaluate the synergistic action of CAPE in radiotherapy sensitivity of NPC cell lines and further elucidate the possible molecular mechanism involved. Materials and methods: CCK-8 assay was used to analyze cell proliferation ability. Colony formation assay was used to evaluate the clonogenic ability and radio-sensitiveness of NPC cells by CAPE treatment. Wound-healing and transwell assay were used to assess the motility of cells. The expression of key molecules of the epithelial-mesenchymal transition (EMT) was determined by western blot analysis and changes in radiation sensitivity were measured by colony-formation assay. cDNA microarray analysis was used to determine differentially expressed genes with and without CAPE treatment, with Gene Ontology enrichment of gene function and KEGG pathways determined. Cell cycle and apoptosis were detected by flow cytometry and western blot analysis. Results: CAPE suppressed the viability of NPC cell lines time- and dose-dependently. It induced apoptosis in NPC cells along with decreased expression of Bcl-XL and increased cleavage of PARP and expression of Bax. G1 phase arrest was induced by CAPE with ower expression of CDK4, CDK6, Rb and p-Rb. The migratory and invasive ability of NPC cells was decreased by the EMT pathway. The irradiation sensitivity of NPC cells was enhanced with CAPE treatment. CAPE specifically inhibited nuclear factor κB (NF-κB) signaling pathway by suppressing p65 subunit translocation from cytoplasm to nucleus. CAPE treatment was synergistic with chemotherapy and radiotherapy. Conclusion: CAPE may inhibit the proliferation and metastasis of NPC cells but enhance radiosensitivity in NPC therapy by inhibiting the NF-κB pathway. CAPE could be a potential therapeutic compound for NPC therapy.

Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients.

Kidney is an important organ for ketone body metabolism. However, the role of abnormal ketone metabolism and its possible function in tumorigenesis of clear cell renal cell carcinoma (ccRCC) have not yet been elucidated. Three differentially expressed key enzymes involved in ketone body metabolism, ACAT1, BDH2, and HMGCL, were screened out between ccRCC and normal kidney tissues using the GEO and TCGA databases.We confirmed that the transcription and protein expression of ACAT1, BDH2, and HMGCL were significantly lower in ccRCC by real-time RT-PCR and IHC assays. Those patients with lower expression of these three genes have a worse outcome. In addition, we demonstrated that ectopic expression of each of these genes inhibited the proliferation of ccRCC cells. The overexpressed ACAT1 and BDH2 genes remarkably impeded the migratory and invasive capacity of ccRCC cells. Furthermore, exogenous ß-hydroxybutyrate suppressed the growth of ccRCC cells in vitro in a dose-dependent manner. Our findings suggest that ACAT1, BDH2, and HMGCL are potential tumor suppressor genes, and constitute effective prognostic biomarkers for ccRCC. Ketone body metabolism might thus be a promising target in a process for developing novel therapeutic approaches to treat ccRCC.