The Clinical and Biological Effects of Receptor Expression-Enhancing Protein 6 in Tongue Squamous Cell Carcinoma.

There are currently no effective biomarkers for the diagnosis and treatment of tongue squamous cell carcinoma (TSCC), which causes a poor 5-year overall survival rate. Thus, it is crucial to identify more effective diagnostic/prognostic biomarkers and therapeutic targets for TSCC patients. The receptor expression-enhancing protein 6 (REEP6), a transmembrane endoplasmic reticulum resident protein, controls the expression or transport of a subset of proteins or receptors. Although it was reported that REEP6 plays a role in lung and colon cancers, its clinical impact and biological role in TSCC are still unknown. The present study aimed to identify a novel effective biomarker and therapeutic target for TSCC patients. Expression levels of REEP6 in specimens from TSCC patients were determined with immunohistochemistry. Gene knockdown was used to evaluate the effects of REEP6 in cancer malignancy (colony/tumorsphere formation, cell cycle regulation, migration, drug resistance and cancer stemness) of TSCC cells. The clinical impact of REEP6 expression and gene co-expression on prognosis were analyzed in oral cancer patients including TSCC patients from The Cancer Genome Atlas database. Tumor tissues had higher levels of REEP6 compared to normal tissues in TSCC patients. Higher REEP6 expression was related to shorter disease-free survival (DFS) in oral cancer patients with poorly differentiated tumor cells. REEP6-knocked-down TSCC cells showed diminished colony/tumorsphere formation, and they also caused G1 arrest and decreased migration, drug resistance and cancer stemness. A high co-expression of REEP6/epithelial-mesenchymal transition or cancer stemness markers also resulted in poor DFS in oral cancer patients. Thus, REEP6 is involved in the malignancy of TSCC and might serve as a potential diagnostic/prognostic biomarker and therapeutic target for TSCC patients.

The activation of EP300 by F11R leads to EMT and acts as a prognostic factor in triple-negative breast cancers.

Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the F11R (F11 receptor) in tumours were inversely correlated to the expression of JAM-2 and JAM-3. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (p = 0.024, hazard ratio = 1.44 [1.05-1.99]). A 50-gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. F11R mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)-enriched (p = 0.0035) and basal-like BCa tumours (p = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (p < 0.001; Taipei Medical University [TMU] cohort, p < 0.001; Kaohsiung Veterans General Hospital [KVGH] cohort) or disease-free survival (p < 0.001 [TMU cohort], p = 0.034 [KVGH cohort]) in patients with BCa. Comparison of F11R levels in different subtypes revealed the association of poor prognosis with high levels of F11R among luminal (p < 0.001 [TMU cohort], p = 0.027 [KVGH cohort]), HER2 positive (p = 0.018 [TMU cohort], p = 0.037 [KVGH cohort]), and triple-negative (p = 0.013 [TMU cohort], p = 0.037 [KVGH cohort]) BCa. F11R-based RNA microarray analysis and Ingenuity Pathway Analysis were successful in profiling the detailed gene ontology of triple-negative BCa cells regulated by F11R. The EP300 transcription factor was highly correlated with F11R in BCa (R = 0.51, p < 0.001). By analysing these F11R-affected molecules with the L1000CDs datasets, we were able to predict some repurposing drugs for potential application in F11R-positive BCa treatment.

Carboxyl-terminal modulator protein facilitates tumor metastasis in triple-negative breast cancer.

Currently, the survival rate for breast cancer is more than 90%, but once the cancer cells metastasize to distal organs, the survival rate is dramatically reduced, to less than 30%. Triple-negative breast cancer accounts for 15-20% of all breast cancers. Triple-negative breast cancer (TNBC) is associated with poor prognostic and diagnostic outcomes due to the limiting therapeutic strategies, relative to non-TNBC breast cancers. Therefore, the development of targeted therapy for TNBC metastasis remains an urgent issue. In this study, high Carboxyl-terminal modulator protein (CTMP) is significantly associated with recurrence and disease-free survival rate in TNBC patients. Overexpression of CTMP promotes migration and invasion abilities in BT549 cells. Down-regulating of CTMP expression inhibits migration and invasion abilities in MDA-MB-231 cells. In vivo inoculation of high-CTMP cells enhances distant metastasis in mice. The metastasis incidence rate is decreased in mice injected with CTMP-downregulating MDA-MB-231 cells. Gene expression microarray analysis indicates the Akt-dependent pathway is significantly enhanced in CTMP overexpressing cells compared to the parental cells. Blocking Akt activation via Akt inhibitor treatment or co-expression of the dominant-negative form of Akt proteins successfully abolishes the CTMP mediating invasion in TNBC cells. Our findings suggest that CTMP is a potential diagnostic marker for recurrence and poor disease-free survival in TNBC patients. CTMP promotes TNBC metastasis via the Akt-activation-dependent pathway.

MAP3K11 facilitates autophagy activity and is correlated with malignancy of oral squamous cell carcinoma.

Autophagy-related 4B (ATG4B) is a protease required for core machinery of autophagy. Phosphorylation of ATG4B promotes autophagy and is correlated with poor outcome of cancer. However, little is known about the upstream kinases for ATG4B phosphorylation and their association with clinical outcomes of cancer patients. Through siRNA library screening, MAP3K11 was identified as a potential kinase that phosphorylates ATG4B and increases its proteolytic activity. Ablation of MAP3K11 attenuated pS383/392-ATG4B protein levels and autophagic flux in oral cancer cells. Moreover, loss of MAP3K11 inhibited oral cancer cell growth, migration/invasion, and synergized starvation-reduced cell viability. MAP3K11 knock-out cancer cells also showed growth inhibition in vivo. Furthermore, the protein level of MAP3K11 was higher in tumor tissues than that in adjacent normal tissues in patients with oral squamous cell carcinoma (OSCC), comprising 179 buccal mucosa squamous cell carcinoma (BMSCC) and 249 tongue squamous cell carcinoma (TSCC). MAP3K11 protein levels were positively correlated with ATG4B and pS383/392-ATG4B levels in patients with OSCC, particularly in TSCC. In addition, high coexpression of MAP3K11 and ATG4B was associated with poor disease-specific survival in BMSCC and TSCC, while high coexpression of MAP3K11 and pS383/392-ATG4B was associated with unfavorable disease-free survival in BMSCC and TSCC. Taken together, our results indicated that MAP3K11 stimulated activity of ATG4B and autophagy, which may confer to malignancy of cancer cells. The expression of MAP3K11 and ATG4B was further associated with poor survival of OSCC, suggesting MAP3K11 could serve as a theranostic target of patients with OSCC.

Effect of EGFR on SQSTM1 Expression in Malignancy and Tumor Progression of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types of cancer. However, the association of EGFR and SQSTM1 in OSCC is still unknown. Our results show that the expression levels of SQSTM1 and EGFR proteins are higher in tumor tissues than in the corresponding tumor-adjacent (CTAN) tissues of OSCC patients. The expression levels of SQSTM1 were positively associated with the EGFR expression level. High co-expression of SQSTM1 and EGFR is associated with poor prognosis in OSCC patients. Moreover, SQSTM1 expression is decreased in EGFR-knockdown cells. Cell growth and invasion/migration are also decreased in cells with single/combined knockdowns of EGFR and SQSTM1 or in SQSTM1-knockdown cells without EGFR kinase inhibitor Lapatinib treatment compared to that in scrambled cells. However, cell growth and invasion/metastasis were not significantly different between the scrambled cells and SQSTM1-knockdown cells in the presence of Lapatinib. This study is the first to indicate the biological roles and clinical significance of SQSTM1 regulation by EGFR in OSCC.

Combined Evaluation of MAP1LC3B and SQSTM1 for Biological and Clinical Significance in Ductal Carcinoma of Breast Cancer.

Breast cancer is the leading cause of cancer death in women worldwide. The microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1 (SQSTM1) are two major markers for autophagy. Increased protein levels of MAP1LC3B and SQSTM1 are considered to be causes of autophagy inhibition or activation in various types of cancers. However, the roles of MAP1LC3B and SQSTM1 in breast cancer are still not clear. Using a tissue microarray from 274 breast invasive ductal carcinoma (IDC) patients, we found that tumor tissues showed higher protein levels of MAP1LC3B and cytoplasmic SQSTM1 in comparison to those in adjacent normal tissues. Moreover, high levels of MAP1LC3B were associated with better survival, including disease-specific survival and disease-free survival (DFS) in IDC patients. Furthermore, high co-expression of MAP1LC3B and SQSTM1 was significantly associated with better DFS in IDC patients. Astonishingly, the autophagy inhibitor accumulated the protein levels of MAP1LC3B/SQSTM1 and enhanced the cytotoxic effects of cisplatin and paclitaxel in MCF7 and BT474 breast cancer cell lines, implying that autophagy inhibition might result in poor prognosis and chemosensitivity in IDC. Taken together, high co-expression of MAP1LC3B and SQSTM1 might serve as a potential diagnostic and prognostic biomarker for IDC patients.

Clinical Significance and the Role of Guanylate-Binding Protein 5 in Oral Squamous Cell Carcinoma.

Guanylate binding protein 5 (GBP5) is the interferon (IFN)-inducible subfamily of guanosine triphosphatases (GTPases) and is involved in pathogen defense. However, the role played by GBP5 in cancer development, especially in oral squamous cell carcinoma (OSCC), is still unknown. Herein, next-generation sequencing analysis showed that the gene expression levels of GBP5 were significantly higher in OSCC tissues compared with those found in corresponding tumor adjacent normal tissues (CTAN) from two pairs of OSCC patients. Higher gene expression levels of GBP5 were also found in tumor tissues of 23 buccal mucosal squamous cell carcinoma (BMSCC)/14 tongue squamous cell carcinoma (TSCC) patients and 30 oral cancer patients from The Cancer Genome Atlas (TCGA) database compared with those in CTAN tissues. Immunohistochemical results showed that protein expression levels of GBP5 were also higher in the tumor tissues of 353 OSCC patients including 117 BMSCC, 187 TSCC, and 49 lip squamous cell carcinoma patients. Moreover, TCGA database analysis indicated that high gene expression levels of GBP5 were associated with poor overall survival in oral cancer patients with moderate/poor cell differentiation, and associated with poor disease-free survival in oral cancer patients with moderate/poor cell differentiation and lymph node metastasis. Furthermore, GBP5-knockdowned cells exhibited decreased cell growth, arrest at G1 phase, and decreased invasion/migration. The gene expression of markers for epithelial-mesenchymal transition and cancer stemness was also reduced in GBP5-silenced oral cancer cells. Taken together, GBP5 might be a potential biomarker and therapeutic target for OSCC patients, especially for those with poor cell differentiation and lymph node metastasis.

Identifying Circulating MicroRNA in Kawasaki Disease by Next-Generation Sequencing Approach.

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs; therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes >2 and <0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-ß, epithelial-mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p < 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.

MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer.

Brian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood-brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

Knowledge, attitude, and barriers regarding prescribing long-term opioids among Taiwan physicians treating officially registered patients with chronic noncancer pain.

BACKGROUND: Prescribing opioids for patients with chronic noncancer pain (CNCP) remains controversial. This study surveyed Taiwanese physicians who were clinically treating CNCP outpatients with long-term opioids. METHODS: Anonymous questionnaires investigating the clinical practices, opioid knowledge, attitude, and barriers regarding the prescription of long-term opioids were delivered to 66 physicians treating CNCP outpatients who were officially registered and monitored by the Taiwan Food and Drug Administration in 2011. RESULTS: All 66 (100%) physicians responded to the survey, comprising 41 (62%) board-certified pain specialists and 25 (38%) nonpain board-certified physicians. Pain specialists treated a greater number of CNCP outpatients and attended more CNCP training courses than nonpain board-certified physicians (97.6% vs. 56.0%, p < 0.001). Most of pain specialists stated that they were familiar with the Taiwan's narcotic regulations for CNCP patients (92.7% vs. 68.0%, p = 0.015). In addition, pain specialists were less likely to skip or reduce the dosage and duration of opioid prescriptions (22.0% vs. 36.0%, p < 0.001). By contrast, nonpain board-certified physicians had significantly less knowledge and a more negative attitude toward opioid prescription. The major perceived barriers were physician's reluctance to prescribe opioids (78% vs. 92%) and an inadequate knowledge of pain management (73% vs. 84%) among all physicians. CONCLUSION: Among the Taiwanese physicians treating the officially registered CNCP patients, nonpain board-certified physicians had fewer patients, less knowledge, and an increased negative attitude toward long-term opioid prescriptions. Better education on chronic pain management is needed for improvement of clinical practice.

UBE2C is a Potential Biomarker for Tumorigenesis and Prognosis in Tongue Squamous Cell Carcinoma.

Ubiquitin-conjugating enzyme 2C (UBE2C) involves in numerous cellular processes and the tumor progression in many cancers. However, its role in oral squamous cell carcinoma (OSCC) is unclear. We aimed to investigate the role and clinical significance of UBE2C in OSCC. The expression levels of UBE2C were examined by immunohistochemistry in 185 buccal mucosa squamous cell carcinomas, 247 tongue squamous cell carcinomas (TSCCs) and 75 lip squamous cell carcinomas. The roles of UBE2C in cell growth, invasion/migration and cancer stemness were also examined in OSCC cells. The expression levels of UBE2C protein were higher in tumor tissues than they were in the corresponding tumor adjacent normal tissues from OSCC patients. Higher UBE2C expression was associated with poor cell differentiation and lymph node invasion in OSCC patients. High UBE2C expression was also correlated with shorter disease-specific survival in TSCC patients having poor cell differentiation, advanced pathological stages, lymph node metastasis as well as receiving radiation therapy. Compared to control cells, OSCC cells in which UBE2C was silenced showed decreased cell proliferation, migration/invasion and colony formation and they exhibited lower expression levels of the following cancer stemness markers-ALDH1/A2, CD44, CD166 and EpCAM. High co-expression levels of UBE2C/CD44, UBE2C/CD166 and UBE2C/EpCAM were associated with poor prognosis in oral cancer patients from The Cancer Genome Atlas database. Our findings indicated that UBE2C might be a potential biomarker for tumorigenesis and prognosis in TSCC.

Author Correction: HSPD1 repressed E-cadherin expression to promote cell invasion and migration for poor prognosis in oral squamous cell carcinoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Guanylate-binding protein 6 is a novel biomarker for tumorigenesis and prognosis in tongue squamous cell carcinoma.

OBJECTIVES: Guanylate-binding protein 6 (GBP6) is a member of the guanylate-binding protein family, and its role in cancer has not yet been reported. We aimed to investigate the clinical significance of GBP6 in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Next-generation sequencing was applied for analyzing differential gene expression profiling between corresponding tumor adjacent normal (CTAN) and tumor tissue from two paired OSCC patients. Real-time PCRs (RT-PCRs) were used to investigate the gene expression level of GBP6 of CTAN and tumor tissue samples from 14 TSCC patients. Immunohistochemistry was used to investigate the protein expression level of GBP6 in tumor tissues and paired CTAN tissues from 488 OSCC patients, including 183 buccal mucosa squamous cell carcinoma (BMSCC), 245 tongue squamous cell carcinoma (TSCC), and 60 lip squamous cell carcinoma (LSCC) patients. RESULTS: Compared with CTAN tissues of OSCC patients, GBP6 is identified as a downregulated gene using the NGS platform, which was confirmed in 14 OSCC patients by RT-PCR. Moreover, protein expression level of GBP6 in tumor tissues was lower than that in CTAN tissues and the low GBP6 expression was correlated with poor cell differentiation/lymph node metastasis in TSCC patients. In addition, TSCC patients with low expression levels of GBP6 had poor disease-specific survival rate. CONCLUSION: The low expression of GBP6 was associated with tumorigenesis and poor prognosis in OSCC patients, especially in TSCC patients. CLINICAL RELEVANCE: GBP6 may serve as a novel favorable diagnostic and prognostic biomarker in TSCC patients.

Prognostic role of RECK in pathological outcome-dependent buccal mucosa squamous cell carcinoma.

BACKGROUND: Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features. MATERIALS AND METHODS: The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models. RESULTS: The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer. CONCLUSION: The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.

HSPD1 repressed E-cadherin expression to promote cell invasion and migration for poor prognosis in oral squamous cell carcinoma.

Buccal mucosa squamous cell carcinoma (BMSCC) is one of major subsites of oral cancer and is associated with a high rate of metastasis and poor prognosis. Heat shock proteins (HSPs) act as potential prognostic biomarkers in many cancer types. However, the role of HSPD1 in oral cancer, especially in BMSCC, is still unknown. Through data analysis with The Cancer Genome Atlas (TCGA), we found the association of HSPD1 gene expression with tumorigenesis and poor prognosis in oral cancer patients. Our cohort study showed that higher HSPD1 protein level was associated with tumorigenesis and poor prognosis in BMSCC patients with lymph node invasion, suggesting that HSPD1 may be involved in tumor metastasis. Moreover, knockdown of HSPD1 induced E-cadherin expression and decreased the migration and invasion of BMSCC cells. In contrast, ectopic expression of HSPD1 diminished E-cadherin expression and promoted the migration/invasion of BMSCC cells. Further, HSPD1 regulated RelA activation to repress E-cadherin expression, enhancing the migration and invasion of BMSCC cells. Furthermore, HSPD1 protein level was inversely correlated with E-cadherin protein level in tumor tissues and co-expression of high HSPD1/low E-cadherin showed a significant association with poor prognosis in BMSCC patients. Taken together, HSPD1 might repress E-cadherin expression and promote metastatic characters of BMSCC cells for poor prognosis of BMSCC patients.

Association of SDF-1 and CXCR4 Polymorphisms With Susceptibility to Oral and Pharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: Long-term exposure to betel quid (BQ)-, cigarette-, and alcohol-induced chronic inflammation is a crucial risk factor for oral and pharyngeal squamous cell carcinoma (OPSCC) progression. We analyzed the genotypes of stromal-cell-derived factor-1 (SDF-1) and CXC-chemokine receptor-4 (CXCR4) and determined the association between their polymorphisms and the risk of OPSCC. MATERIALS AND METHODS: This study consisted of 452 patients with pathologically proved OPSCC and 424 sex- and age-matched cancer-free controls. The genotypes of SDF-1 and CXCR4 were detected through the TaqMan real-time polymerase chain reaction (PCR) method. RESULTS: Our data indicated that the C allele and C/C genotypes of CXCR4 were significantly associated with OPSCC [adjusted odds ratio (AOR)=1.41, 95% confidence interval (CI):1.02-1.96, p=0.037 and AOR=1.51, 95% CI:1.05-2.17, p=0.028, respectively] and OSCC (AOR=1.41, 95%CI:1.00-2.00, p=0.049 and AOR=1.49, 95%CI:1.01-2.20, p=0.044, respectively) risk. Patients with genetic polymorphisms of the genotype combination SDF-1/CXCR4 had a higher risk of OSCC (p trend=0.033). We analyzed the effects of CXCR4 genetic variants on susceptibility to OPSCC in patients with different risk habits of BQ chewing, tobacco smoking and alcohol consumption, and revealed that C/T+T/T genotypes exerted an increased risk only in patients with one (AOR=2.68, p=0.036) or two risk habits (AOR=2.02, p=0.027) compared to patients with the C/C genotype. CONCLUSION: We concluded that CXCR4 C>T can be used as a genetic marker of susceptibility to OPSCC, particularly in OPSCC patients with one or two types of risk habits with a synergistic effect.

Differential clinical significance of COL5A1 and COL5A2 in tongue squamous cell carcinoma.

BACKGROUND: Type V collagen (COL5), in the functional heterotrimer [α1(V)2 α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. MATERIALS AND METHODS: The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate. RESULTS: Expression level of COL5A1 was significantly increased in tumor tissues (P < 0.001) compared to that in corresponding adjacent normal tissues. High expression level of COL5A1 was associated with advanced pathological stage (III, IV, P = 0.015) and lymph node metastasis (P = 0.005) of TSCC patients. High expression level of COL5A1 was also correlated with poor disease-specific survival (DSS, P = 0.001) and disease-free survival (DFS, P = 0.003) in TSCC patients. However, high expression level of COL5A2 was correlated with better DFS in TSCC patients (P = 0.043). Moreover, co-expression level of high (COL5A1)2 /low (COL5A2) heterotrimer was correlated with worse DSS (P = 0.004) and DFS (P = 0.004). CONCLUSION: COL5A1 is an unfavorable factor for tumorigenesis, clinicopathological outcomes, and prognosis, whereas COL5A2 is only a favorable factor for prognosis in TSCC. The co-expression of high (COL5A1)2/low (COL5A2) heterotrimer is a more potential unfavorable factor for prognosis in TSCC.

Low C6orf141 Expression is Significantly Associated with a Poor Prognosis in Patients with Oral Cancer.

C6orf141 (Chromosome 6 open reading frame 141) is a novel gene, and its role in oral cancer progression remains unclear. C6orf141 expression in oral squamous cell carcinoma (OSCC) and adjacent normal tissues from 428 patients was examined through immunohistochemistry (IHC). Our results revealed that C6orf141 expression was significantly reduced in OSCC compared with adjacent normal tissues. Low C6orf141 expression was significantly associated with a poor American Joint Committee on Cancer pathological stage (P < 0.001), T classification (P = 0.002), and pN stage (P = 0.032). Kaplan-Meier curves revealed that low C6orf141 expression was significantly associated with shorter disease-specific survival (DSS) in patients with OSCC (log-rank P = 0.007). Multivariate analysis indicated that low C6orf141 expression was an independent prognostic biomarker for DSS (adjusted hazard ratio = 1.34; 95% confidence interval = 1.10-1.81; P = 0.05). Additionally, ectopic C6orf141 expression could significantly suppress oral cancer cell proliferation, colony formation, and migratory and invasive abilities. Xenograft tumor growth assay revealed that C6orf141 could significantly suppress oral tumor growth in vivo. Our results suggest that C6orf141 plays a novel tumor-suppressive role in oral cancer cell growth and motility. Furthermore, C6orf141 dysfunction could be a potential prognostic biomarker for OSCC and provide new therapeutic strategies in the future.

Knowledge, Attitude and Practice Survey of Prescribing Opioids for Chronic Noncancer Pain in Taiwan-Comparison of Pain and Non-Pain Physicians.

BACKGROUND: Prescribing opioids for chronic noncancer pain (CNCP) has been strictly regulated in Taiwan. This study was undertaken to survey pain and non-pain related physicians' knowledge, attitudes, and practices regarding prescribing opioids for CNCP. METHODS: A questionnaire survey was conducted in this comparison study. All 66 physicians who were treating officially registered CNCP outpatients were visited and completed anonymous questionnaires. The other physicians (anesthesiologists, oncologists, and non-pain physicians) were surveyed by a mailed questionnaire. RESULTS: A total of 266 (75%) questionnaires were received from 355 board-certified physicians. More CNCP physicians (81.8%) and anesthesiologists (69.7%) had received prior CNCP-related training courses than had oncologists (21.2%) and non-pain physicians (10.3%). Varied proportions of physicians by type were unfamiliar with the Taiwan opioid regulations (16.7-86.8%) and would accordingly skip or reduce dosage of opioid prescriptions (27.3-73.5%). In addition, non-pain physicians had a significantly lower knowledge level, more negative attitudes, and greater hesitation about prescribing opioids compared to the pain-related physicians (P < 0.001). CNCP physicians who had received CNCP-related training courses had a higher knowledge score than did those not receiving training (P = 0.002). Overall, the leading barriers for prescribing opioids were inadequate knowledge of pain management (76%), physician reluctance (73%), and family reluctance (78%). CONCLUSION: There are substantial knowledge gaps, negative attitudes, and hesitation toward prescribing long-term opioids for CNCP patients by physicians in Taiwan, suggesting that efforts are needed to improve postgraduate education regarding adequate opioid management for CNCP.