Erratum: Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma: Erratum.

[This corrects the article DOI: 10.7150/ijbs.54014.].

Parallel phonological processing of Chinese characters revealed by flankers tasks.

An important and extensively researched question in the field of reading is whether readers can process multiple words in parallel. An unresolved issue regarding this question is whether the phonological information from foveal and parafoveal words can be processed in parallel, i.e., parallel phonological processing. The present study aims to investigate whether there is parallel phonological processing of Chinese characters. The original and the revised flankers tasks were applied. In both tasks, a foveal target character was presented in isolation in the no-flanker condition, flanked on both sides by a parafoveal homophone in the homophone-flanker condition, and by a non-homophonic character in the unrelated-flanker condition. Participants were instructed to fixate on the target characters and press two keys to indicate whether they knew the target characters (lexical vs. non-lexical). In the original flankers task, the stimuli were presented for 150 ms without a post-mask. In the revised flankers task, we set the stimulus exposure time (duration of the stimuli plus the blank interval between the stimuli and the post-mask) to each participant's lexical decision threshold to prevent participants from processing the target and flanker characters serially. In both tasks, reaction times to the lexical targets were significantly shorter in the homophone-flanker condition than in the unrelated-flanker condition, suggesting parallel phonological processing of Chinese characters. In the revised flankers task, accuracy rates to the lexical targets were significantly lower in the unrelated-flanker condition compared to the homophone-flanker condition, further supporting parallel phonological processing of Chinese characters. Moreover, reaction times to the lexical targets were the shortest in the no-flanker condition in both tasks, reflecting the attention distribution over both the target and flanker characters. The findings of this study provide valuable insights into the parallel processing mechanisms involved in reading.

Overexpression of NRP1 is Associated with Poor Prognosis via Accelerating Immunosuppression in Head and Neck Squamous Cell Carcinoma.

Background: Neuropilin-1 (NRP1) is a significant molecular structure that participates in many diseases progress including malignant tumors. However, its role in head and neck squamous cell carcinoma (HNSCC) remains to be uncovered. In this study, we determined the function of NRP1 as a crucial biomarker in proliferation, metastasis and immunosuppression in HNSCC. Methods: We collected samples of normal tissues (n = 18) and HNSCC tissues (n = 202) for immunohistochemical staining of NRP1 and evaluated its correlation to clinical prognostic characteristics. Furthermore, we enrolled 37 HNSCC patients received immune checkpoint blockade (ICB) treatment with defined therapeutic effects records. The biological process, signal pathways, and immune infiltration relevance to NRP1 were analyzed utilized transcriptome data from The Cancer Genome Atlas (TCGA). Results: The NRP1 protein expression was significantly upregulated in HNSCC tissue and was associated with T stage, N stage, histological differentiation, recurrence and NRP1 expression. The high expression of NRP1 indicated poor survival rate and was found to be an independent prognosis factor. Enrichment analysis showed that NRP1 was associated with cell adhesion, extracellular matrix organization, homophilic cell adhesion via plasma membrane in biological process and neuroactive ligand-receptor interaction, protein digestion and absorption, calcium signal pathways. Moreover, NRP1 mRNA level was found positively correlated to cancer associated fibroblast cells, Treg cells and macrophage/monocyte cells. Conclusion: NRP1 might be likely to develop into a potential immunoregulation target as well as a predictive biomarker in HNSCC immune treatment.

TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling.

BACKGROUND: Drug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC. METHODS: We performed survival and gene set variation analyses based on HNSCC cohorts and identified the critical role of tumor necrosis factor alpha-induced protein 2 (TNFAIP2) in cisplatin-based chemotherapy resistance. Half-maximal inhibitory concentration (IC50) examination, colony formation assays and flow cytometry assays were conducted to examine the role of TNFAIP2 in vitro, while xenograft models in nude mice and 4-nitroquinoline N-oxide (4NQO)-induced HNSCC models in C57BL/6 mice were adopted to verify the effect of TNFAIP2 in vivo. Gene set enrichment analysis (GSEA) and coimmunoprecipitation coupled with mass spectrometry (Co-IP/MS) were performed to determine the mechanism by which TNFAIP2 promotes cisplatin resistance. RESULTS: High expression of TNFAIP2 is associated with a poor prognosis, cisplatin resistance, and low reactive oxygen species (ROS) levels in HNSCC. Specifically, it protects cancer cells from cisplatin-induced apoptosis by inhibiting ROS-mediated c-JUN N-terminal kinase (JNK) phosphorylation. Mechanistically, the DLG motif contained in TNFAIP2 competes with nuclear factor-erythroid 2-related factor 2 (NRF2) by directly binding to the Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), which prevents NRF2 from undergoing ubiquitin proteasome-mediated degradation. This results in the accumulation of NRF2 and confers cisplatin resistance. Positive correlations between TNFAIP2 protein levels and NRF2 as well as its downstream target genes were validated in HNSCC specimens. Moreover, the small interfering RNA (siRNA) targeting TNFAIP2 significantly enhanced the cisplatin treatment effect in a 4NQO-induced HNSCC mouse model. CONCLUSIONS: Our results reveal the antioxidant and cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target in improving the cisplatin treatment effect, particularly for patients with cisplatin resistance.

Development and validation of a nomogram to predict occult cervical metastasis in early oral squamous cell carcinoma.

Background: Lack of adequate objectivity and universality, available models are still difficult to be applied to clinical practice in predicting occult cervical metastasis of early oral squamous cell carcinoma (OSCC). Taking abnormal metabolic state into consideration, the current model is helpful to distinguish those patients with or without occult cervical metastasis. Methods: This study retrospectively analyzed 330 OSCC patients initially diagnosed cT1-2N0M0 stage and received neck dissection from January 2020 to July 2022. The occult cervical metastasis was identified by pathological examination.. After screening independent risk factors using logistic regression, patients were divided into training and validation cohorts at the ratio of 2:1 randomly, and a novel diagnostic model was constructed. Performances of this model were evaluated by the area under the curve (AUC), calibrating curve, decision curve analysis (DCA) and clinical impact curve (CIC). Results: Of the 330 included patients {age mean [standard deviation (SD)], 61.24 (12.99) years; 202 (61.2%) males}, 49 (14.8%) had occult nodal metastasis. Five variables, including body mass index (BMI) [high odds ratio (OR): 1.132; 95% confidence interval (CI): 1.019-1.258, P=0.021], primary tumor site (tongue & floor of mouth (TF) OR: 3.756; 95% CI: 1.295-10.898, P=0.015), depth of invasion (DOI) (5-10 mm OR: 2.973; 95% CI: 1.266-6.981; P=0.012), pathological differentiation (Poor differentiation OR: 2.65; 95% CI: 1.341-5.239; P=0.005), and diabetes (OR: 3.123; 95% CI: 1.23-7.929; P=0.017) were screened to establish the predictive model. In training cohort (n=220), this model achieved an AUC of 0.814 and had a sensitivity of 78.1% and specificity of 70.2%. Calibration plots showed favorable consistency between the prediction of the model and actual observations (Hosmer-Lemeshow value >0.05). Decision curve analysis (DCA) and clinical impact curve (CIC) showed the model was clinically useful and had better discriminative ability under the threshold probability of 0.5. Above evaluations were verified in the validation cohort (n=110). Compared to previous reported models, the concordance index (C-index), net reclassification index (NRI), and integrated discrimination improvement (IDI) values were superior in both training and validation cohorts (P<0.05). Conclusions: This constructed model might have reference value for clinicians in making neck management decisions of early OSCC patients.

Preliminary Study on Human Adipose Stem Cells Promoting Skin Wound Healing through Notch Signaling Pathway.

BACKGROUND: Mesenchymal stem cells (MSCs) have been documented as possible candidates for wound healing treatment because their use could reinforce the regenerative capacity of many tissues. Human adipose stem cells (hADSCs) have the advantages of easy access, large quantity and easy operation. They can be fully applied in the treatment of skin wounds. OBJECTIVE: In this study, we aim to explore the roles and potential mechanisms of hADSCs in cutaneous wound healing. METHODS: hADSCs were obtained from human subcutaneous fat. Adipocytes and osteocytes differentiated from hADSCs were determined by staining with Oil Red O and alkaline phosphatase (ALP), respectively. We assessed the effects of hADSCs and hADSC conditional medium (CM) on wound healing in an injury model of mice. Then, we investigated the biological effects of hADSCs on human keratinocytes HaCAT cells in vitro. RESULTS: The results showed that hADSCs could be successfully differentiated into osteogenic and lipogenic cells. hADSCs and hADSCs-CM significantly promote skin wound healing in vivo. hADSCs significantly promoted HaCAT cell proliferation and migration by activating the Notch signaling pathway and activated the AKT signaling pathway by Rps6kb1 kinase in HaCAT cells. In addition, we found that hADSCs-mediated activation of Rps6kb1/AKT signaling was dependent on the Notch signaling pathway. CONCLUSION: We demonstrated that hADSCs can promote skin cell-HaCAT cell proliferation and migration via the Notch pathway, suggesting that hADSCs may provide an alternative therapeutic approach for the treatment of skin injury.

Regulation of Semaphorin3A in the process of cutaneous wound healing.

Semaphorin 3A (Sema3A) has been recognized as a crucial regulator of morphogenesis and homeostasis over a wide range of organ systems. However, its function in cutaneous wound healing is poorly understood. In our study, we demonstrated that Sema3A adenovirus plasmids transfection limited keratinocyte proliferation and decreased migrative capacity as assessed by in vitro wound healing assay. Sema3A transduction inhibited TGF-ß1-mediated keratinocyte migration and EMT process. Besides, we applied mice with K14-Cre-mediated deletion of Sema3A and found that Sema3A depletion postponed wound closure with decreased re-epithelialization and matrix growth. Contrary to the results obtained with full-length Sema3A plasmids transfection, increased keratinocyte migration with recombinant Sema3A proteins resulted in quicker closure of the wounding area after a scratch. Further, exogenously applied recombinant Sema3A worked with EGF to maintain the activation of EGFR by interacting with NRP1 and thereby regulated the internalization of the EGFR-NRP1 complex. Taken together, these results indicated a paradoxical role of autonomous and non-autonomous Sema3A expression during wound healing. Combined administration of recombinant EGF and Sema3A proteins could accelerate the process of wound repair, thus providing promising treatment prospects in the future.

Identification of Biomarkers Related to Regulatory T Cell Infiltration in Oral Squamous Cell Carcinoma Based on Integrated Bioinformatics Analysis.

Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignancies worldwide. More recently, the administration of immune checkpoint inhibitors has opened up more possibilities for cancer treatment. Methods: We utilized a weighted gene co-expression network and the single sample gene set enrichment analysis (ssGSEA) algorithm in the TCGA database and identified a module highly correlated with regulatory T cell (Treg) abundance in OSCC. Subsequently, we verified the results by tissue microarrays and utilized immunohistochemical staining (IHC) to test the relationship between the expression level and clinicopathological staging. CCK-8, transwell, and wound healing assays were utilized to detect the functions of OSCC cells. Results: LCK, IL10RA, and TNFRSF1B were selected as biomarkers related to regulatory T cell infiltration. IHC staining showed significantly increased expression of LCK, IL10RA or TNFRSF1B in OSCC patients, and the expression levels were associated with tumor stage, lymph node metastasis, pathological stage, clinical status and the overall survival. In vitro experiments showed that LCK, IL10RA or TNFRSF1B knockdown efficiently impaired the proliferative, migrative, and invasive capacity in OSCC cell lines. Conclusion: We performed a series of bioinformatics analyses in OSCC and identified three oncogenic indicators: LCK, IL10RA, TNFRSF1B. These findings uncovered the potential prognostic values of hub genes, thus laying foundations for in-depth research in OSCC.

Perineural invasion, lactate dehydrogenase, globulin, and serum sodium predicting occult metastasis in oral cancer.

OBJECTIVE: This study aimed to develop a nomogram to predict the neck occult metastasis in early (T1-T2 cN0) oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The nomogram was developed in a training cohort of 336 early OSCC patients and was validated in a validation cohort including 88 patients. Independent predictors were calculated by univariate and multivariate logistic regression analyses. RESULTS: In univariate logistical regression analysis, gender, perineural invasion (PNI), blood vessel invasion, mean corpuscular hemoglobin, aspartate aminotransferase, prealbumin, globulin (GLO), lactate dehydrogenase (LDH), serum sodium (NA), and serum chloride were significant associated with neck occult metastasis. Multivariate logistical regression analysis identified PNI (p < .001), LDH (p = .003), GLO (p = .019), and NA (p = .020) as independent predictors of neck occult metastasis. Cut-off values for LDH, GLO, and NA obtained from AUC were 142.5, 26.35, and 139.5, respectively. The nomogram based on PNI and categorical GLO, LDH, and NA exhibited a strong discrimination, with a C-indexes of 0.748 (95%CI = 0.688 to 0.810) in the training cohort and 0.751 (95%CI = 0.639 to 0.863) in the validation cohort. CONCLUSIONS: A nomogram based on PNI, LDH, GLO, and NA for predicting the risk of neck lymph nodes occult metastasis in OSCC could help surgeons with therapy decision-making.

Cytoplasmic eIF6 promotes OSCC malignant behavior through AKT pathway.

BACKGROUND: Eukaryotic translation initiation factor 6 (eIF6), also known as integrin ß4 binding protein, is involved in ribosome formation and mRNA translation, acting as an anti-association factor. It is also essential for the growth and reproduction of cells, including tumor cells. Yet, its role in oral squamous cell carcinoma (OSCC) remains unclear. METHODS: The expression characteristics of eIF6 in 233 samples were comprehensively analyzed by immunohistochemical staining (IHC). Effects of eIF6 over-expression and knockdown on cell proliferation, migration and invasion were determined by CCK-8, wound healing and Transwell assays. Western blot, immunofluorescence (IF) and co-immunoprecipitation (co-IP) were performed for mechanical verification. RESULTS: We found that cytoplasmic eIF6 was abnormally highly expressed in OSCC tissues, and its expression was associated with tumor size and the clinical grade. Amplification of eIF6 promoted the growth, migration and invasion capabilities of OSCC cell lines in vitro and tumor growth in vivo. Through Western blot analysis, we further discovered that eIF6 significantly promotes epithelial-mesenchymal transformation (EMT) in OSCC cells, while depletion of eIF6 can reverse this process. Mechanistically, eIF6 promoted tumor progression by activating the AKT signaling pathway. By performing co-immunoprecipitation, we discovered a direct interaction between endogenous eIF6 and AKT protein in the cytoplasm. CONCLUSION: These results demonstrated that eIF6 could be a new therapeutic target in OSCC, thus providing a new basis for the prognosis of OSCC patients in the future. Video abstract.

Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling.

Ubiquitin D (UBD) is highly upregulated in many cancers, and plays a pivotal role in the pathophysiological processes of cancers. However, its roles and underlying mechanisms in oral squamous cell carcinoma (OSCC) are still unclear. In the present study, we investigated the role of UBD in patients with OSCC. Quantitative real-time polymerase chain reaction and Western blot were used to measure the expression of UBD in OSCC tissues. Immunohistochemistry assay was used to detect the differential expressions of UBD in 244 OSCC patients and 32 cases of normal oral mucosae. In addition, CCK-8, colony formation, wound healing and Transwell assays were performed to evaluate the effect of UBD on the cell proliferation, migration, and invasion in OSCC. Furthermore, a xenograft tumor model was established to verify the role of UBD on tumor formation in vivo. We found that UBD was upregulated in human OSCC tissues and cell lines and was associated with clinical and pathological features of patients. Moreover, the overexpression of UBD promoted the proliferation, migration and invasion of OSCC cells; however, the knockdown of UBD exerted the opposite effects. In this study, our results also suggested that UBD promoted OSCC progression through NF-κB signaling. Our findings indicated that UBD played a critical role in OSCC and may serve as a prognostic biomarker and potential therapeutic target for OSCC treatment.

Immune landscape and subtypes in primary resectable oral squamous cell carcinoma: prognostic significance and predictive of therapeutic response.

BACKGROUND: Immune landscape of cancer has been increasingly recognized as a key feature affecting disease progression, prognosis and therapeutic response. Here, we sought to comprehensively characterize the patterns of tumor-infiltrating immune cells (TIIs) in primary oral squamous cell carcinoma (OSCC) and develop immune features-derived models for prognostication and therapeutic prediction. METHODS: A total number of 392 patients with OSCC receiving ablative surgery at three independent centers were retrospectively enrolled and defined as training, testing and validation cohorts. Detailed features of 12 types of TIIs at center of tumor and invasive margin were assessed by immunohistochemistry coupled with digital quantification. TIIs abundance in OSCC was also estimated by bioinformatics approaches using multiple publicly available data sets. Prognostic models based on selected immune features were trained via machine learning approach, validated in independent cohorts and evaluated by time-dependent area under the curves and concordance index (C-index). Immune types of OSCC were further identified by consensus clustering and their associations with genetic, molecular features and patient survival were clarified. RESULTS: Patterns of TIIs infiltration varied among patients and dynamically evolved along with tumor progression. Prognostic models based on selected TIIs were identified as efficient and sensitive biomarkers to stratify patients into subgroups with favorable or inferior survival as well as responders or non-responders to postoperative radiotherapy or immunotherapy. These models outperformed multiple conventional biomarkers and immune-related scores in prognostic prediction. Furthermore, we identified two main immune subtypes of OSCC (immune-hot and immune-cold) which harbored characteristic TIIs infiltrations and genomic and molecular features, and associated with patient survival. CONCLUSIONS: Our results delineated immune landscape and subtypes in OSCC, consolidated their clinical values as robust biomarkers to predict patient survival and therapeutic benefits and reinforced key roles of TIIs and tumor-immune interactions underlying oral tumorigenesis, ultimately facilitating development of tailed immunotherapeutic strategies.

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma.

MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

Distribution of Chinese traditional villages and influencing factors for regionalization / Distribuição das aldeias tradicionais chinesas e fatores de influência para a regionalização

ABSTRACT: Traditional Villages (TVs) are typical and representative of the agricultural civilization in millions of Chinese villages. The distribution of TVs shows spatial heterogeneity, based on the complexity and diversity of several influencing factors. In this study, 6,819 Chinese TVs were identified and the influencing factors that affect their distribution were screened in terms of three indicator groups: climatic, geographic, and humanity-related factors. Additionally, the K-means clustering algorithm clustered the TVs into different distribution regions. The quantitative relationships between the dominant influencing factors of different distribution regions were revealed to ensure a lucid understanding of the regional distribution of TVs. The results indicated that 1) climatic factors have the greatest impact on the spatial distribution of TVs, followed by geographic factors, particularly the elevation, and then by human factors, of which ethnic distribution played a relatively important role. 2) Twenty-one TV clustering distributions were obtained, which were classified into eight regions of TV distribution with different dominant influencing factors. Management and protective strategies were formulated based on the attribute analysis of influencing factors in each region. The obtained results delineated homogeneous TV distribution regions via the clustering method to achieve an accurate statistical analysis of the influencing factors. This study proposes a new perspective and reference for managing and protecting the diversity, continuity, and integrity of TVs across administrative regions.

RESUMO: As aldeias tradicionais (TVs) são típicas e representativas da civilização agrícola em milhões de comunidades chinesas. A distribuição das TVs mostra heterogeneidade espacial, baseada na complexidade e diversidade de diversos fatores influenciadores. Neste estudo, 6.819 TVs chinesas foram identificadas e os fatores que influenciam sua distribuição foram analisados em termos de três grupos de indicadores: fatores climáticos, geográficos e relacionados à humanidade. Além disso, o algoritmo de agrupamento K-means agrupou as TVs em diferentes regiões de distribuição. As relações quantitativas entre os fatores de influência dominantes de diferentes regiões de distribuição foram reveladas para garantir uma compreensão lúcida da distribuição regional de TVs. Os resultados indicam que 1) os fatores climáticos têm maior impacto na distribuição espacial das TVs, seguidos dos geográficos, em particular da elevação, e depois dos humanos, nos quais a distribuição étnica teve um papel relativamente importante; 2) foram obtidas as vinte e uma distribuições de agrupamento de TV, as quais foram classificadas em oito regiões de distribuição de TV com diferentes fatores de influência dominante. Estratégias de manejo e proteção foram formuladas com base na análise de atributos dos fatores influenciadores de cada região. Os resultados obtidos delinearam regiões homogêneas de distribuição de TV por meio do método de agrupamento para obter uma análise estatística precisa dos fatores de influência. Este estudo propõe uma nova perspectiva e referência para a gestão e proteção da diversidade, continuidade e integridade das TVs nas regiões administrativas.

Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma.

Our group previously identified that the NOTCH1 Abruptex domain contains the most mutations in Chinese OSCC patients, including a hotspot mutation (C1133Y). FBXW7 is an E3 ubiquitin ligase that regulates a network of proteins, including NOTCH1, via degradation. In this study, we first described the co-localization of isoform specific FBXW7-FBXW7ß and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7ß in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7ß significantly attenuated tumor growth. Meanwhile, FBXW7ß reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1C1133Y mutation. FBXW7ß downregulated the stability of NOTCH1C1133Y protein and promoted protein ubiquitination. This was the first time that we selected a NOTCH1 hotspot mutation detected in clinical samples and identified the function of FBXW7ß that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7ß and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.

CMTM6 promotes cell proliferation and invasion in oral squamous cell carcinoma by interacting with NRP1.

Previous studies have identified that both CKLF-like MARVEL transmembrane domain-containing member (CMTM6) and Neuropilin-1 (NRP1) played an essential part in regulating tumorigenesis and immune response. However, the potential connection between CMTM6 and NRP1 in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we investigated the clinicopathologic significance of CMTM6 and NRP1 in OSCC. We examined the co-expression of CMTM6 and NRP1 in both OSCC tissues and cell lines. Co-overexpression of CMTM6 and NRP1 was generally highly expressed in cancer tissues and is associated with poor prognosis. Gain- and loss-of-function assays confirmed the oncogenic properties of CMTM6 in OSCC cells. Depletion of NRP1 abrogated tumorigenesis induced by CMTM6. By performing co-immunoprecipitation (co-IP), we discovered a potential interaction between CMTM6 and NRP1. Meanwhile, the stability of CMTM6 was significantly decreased in the NRP1-silencing cells, indicating the involvement of NRP1 in the degradation process of CMTM6. The crosstalk between CMTM6 and NRP1 provided a new insight into the progression of OSCC, which may indicate an alternative strategy for OSCC treatment.

Prognostic value of log odds of positive lymph nodes in patients with resectable oral squamous cell carcinoma.

OBJECTIVES: Log odds of positive lymph nodes (LODDS) was reported to be significantly associated with prognosis in several malignant tumors. However, few are the studies on the correlation between LODDS and overall survival (OS) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: A retrospective study including 233 patients with OSCC during 2009 to 2013 was conducted. We probed the correlation between clinicopathological factor, LODDS, lymph node ratio (LNR), pN and OS. The potential prognostic factor and the independent factor were calculated using univariate analysis and multivariate analysis respectively. The goodness of fit and the discriminability was analyzed with Somer's D value, Nagelkerke R2 index, and Akaike information criterion (AIC). Kaplan-Meier survival curve of OS was contrasted by log-rank test in LODDS, LNR and pN, respectively. RESULTS: According to the X-tile, the cut-off values are -1.491 and -0.763 for LODDS, 0.024 and 0.133 for LNR. LODDS, LNR and pN were significantly correlated with OS by univariate analysis (P < 0.001). Multivariate analysis demonstrated LODDS, LNR and pN as an independent prognostic factors for OS (P < 0.01). Compared with pN and LNR models, LODDS showed the strongest predictive power. LODDS was superior to LNR and pN in predicting outcomes in patients with no positive lymph nodes and inadequate neck dissection. CONCLUSION: LODDS would be incorporated into future N classification, which may be conducive to discern the prognosis of OSCC and make a decision of adjuvant therapy in clinical practice.

Identification of extracellular vesicles-transported miRNAs in Erlotinib-resistant head and neck squamous cell carcinoma.

Erlotinib is an oral tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) pathway. Although our previous study has proved the efficacy of Erlotinib in head and neck squamous cell carcinoma (HNSCC), it has also demonstrated poor clinical response rates and disappointing results in clinical trials for HNSCC to date. In this study, we discovered elevated cell proliferation and invasion ability in erlotinib-resistant HNSCC cells. The contributions of miRNAs within extracellular vesicles (EVs) during the formation of chemoresistance were investigated in this study. Among up-regulated miRNAs in EVs derived from resistant cells, miR-7704, miR-21-5p and miR-3960 showed the most pro-tumorigenic alterations after transfection. Conversely, let-7i-5p, miR-619-5p and miR-30e-3p demonstrated tumor suppressive effects. By performing qRT-PCR and Western blot analysis, we found Vimentin played a pivotal role in modulating erlotinib resistance. Additionally, immune system was highlighted in the GO and KEGG analyses. Transfection of miR-7704, miR-21-5p significantly elevated CTLA-4 and LAG3 mRNA levels. Meanwhile, miR-3960 increased the relative mRNA expression of TIM3 in HNSCC cells. Transfection of let-7i-5p, miR-619-5p and miR-30e-3p decreased these checkpoint factors. To conclude, the present study described the roles of EVs-transmitted miRNAs on erlotinib resistance. Targeting the disregulated immune system could be the effective method to overcome erlotinib-resistance in HNSCC cells.

MiR-34a inhibits the proliferation, migration, and invasion of oral squamous cell carcinoma by directly targeting SATB2.

In various kinds of carcinomas, the special AT-rich sequence-binding protein 2 (SATB2) with its atypical expression promotes the metastasis and progression of the tumor, though in the oral squamous cell carcinoma (OSCC) its inherent mechanism and the status of SATB2 remain unclear. The role played by the SATB2 expression in the OSCC cell lines and tissue samples in the target of miR-34a downstream is the intended endeavor of this study. In te OSCCs the miR-34a expression was determined by quantitative real-time polymerase chain reaction (q-PCR), while the SATB2 expression in the cell lines and tissue samples in OSCC was analyzed with the q-PCR and the western blot. Studies in both in vitro and in vivo of the effects of miR-34a on the initiation of OSCC were conducted. As a direct target of the miR-34a the SATB2 was verified with the luciferase reporter assay. In cases where the miR-34a levels were low, the SATB2 in OSCCs seemed to be overexpressed. Besides, both in the in vitro and in vivo a suppression of migration, invasion, and cell growth was caused by miR-34a by down regulating the SATB2 expression. The SATB2 being a direct target of miR-34a was confirmed by the cotransfection of miR-34a mimics specifically the decrease in the expression of luciferase of SATB2-3'UTR-wt reporter. As a whole, our study confirmed the inhibition of miR-34a in the invasion, proliferation, and migration of the OSCCs, playing a potential tumor suppressor role with SATB2 as its downstream target.

Neoadjuvant dose-modified docetaxel in squamous cell carcinoma of the head and neck: A phase 3 study.

OBJECTIVE: To evaluate the efficacy and safety of dose-modified docetaxel plus cisplatin and 5-fluorouracil (TPF) in Chinese patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: This Phase III, open-label, multi-center study included Chinese adults with previously untreated TNM Stage III or IV SCCHN (NCT00995293). Patients were randomized (1:1) to induction chemotherapy with TPF (docetaxel 60 mg/m2 and cisplatin 60 mg/m2 on day 1 and 5-FU 750 mg/m2  per day continuous IV infusion on days 1-5) or PF (cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2  per day on days 1-5) every 3 weeks for 3-4 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS in the TPF (n = 108) and PF (n = 111) groups was 400 days and 342 days (HR = 0.75; 95% CI, 0.53─1.06; p = .227), respectively. Overall response rate was higher for TPF versus PF (76.3% vs. 52.9%; p = .001), although this equalized following radiotherapy (75.0% vs. 73.9%). In the TPF and PF groups, ≥1 treatment-emergent adverse event was experienced by 104 (94.5%) and 110 (93.2%) patients, respectively. CONCLUSION: Adding dose-modified docetaxel to PF did not significantly improve PFS but may increase anti-tumor activity in Chinese patients with locally advanced SCCHN.