En-Hao Yu

The Association between Genetic Polymorphism and the Processing Efficiency of miR-149 Affects the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma

MicroRNAs (miRNAs) play important roles in modulating the neoplastic process of cancers including head and neck squamous cell carcinoma (HNSCC). A genetic polymorphism (rs2292832, C>T) has been recently identified in the precursor of miR-149; nevertheless its clinicopathological implications remain obscure. In this study, we showed that miR-149 is down-regulated in HNSCC compared to normal mucosa and this is associated with a poorer patient survival. In addition, HNSCC patients with the T/T genotype have more advanced tumors and a worse prognosis. Multivariate analysis indicated that patients carried the T/T genotype have a 2.81-fold (95% CI: 1.58–4.97) increased risk of nodal metastasis and 1.66-fold (95% CI: 1.05–2.60) increased risk of mortality compared to other groups. T/T genotype also predicted the worse prognosis of buccal mucosa carcinoma subset of HNSCC. In vitro analysis indicated that exogenous miR-149 expression reduces the migration of HNSCC cells. Moreover, HNSCC cell subclones carrying the pri-mir-149 sequence containing the T variant show a low processing efficacy when converting the pre-mir-149 to mature miR-149. These findings suggest that miR-149 suppresses tumor cell mobility, and that the pre-mir-149 polymorphism may affect the processing of miR-149, resulting in a change in the abundance of the mature form miRNA, which, in turn, modulates tumor progression and patient survival.

Histopathological factors affecting nodal metastasis in tongue cancer: analysis of 94 patients in Taiwan

The overall prognosis for tongue cancer patients in Taiwan is unpredictable, even when patients are treated following the guidelines according to TNM stages. In order to determine the optimal treatment modality for tongue cancer in Taiwan the authors aimed to correlate histopathological parameters with neck nodal metastasis. A retrospective analysis of 94 patients with different stages of tongue cancer treated in the Taipei Veterans General Hospital was performed. All 94 patients were clinically diagnosed with stage I-IV tongue cancer before surgery and received primary tumor-wide excision and neck dissection. There were 42 (45%) patients with nodal metastasis. Univariate analysis revealed that cases of tongue cancer with moderate or poor differentiation, an invasion depth more than 3mm and positive perineural invasion or lymphovascular permeation at the time of presentation may be subject to a higher incidence of neck nodal metastasis. An elective neck dissection or neck treatment should be considered if these histopathological risk factors are present. Cases of tongue cancer with these risk factors also warrant close follow-up after surgery.

Detection of copy number amplification of cyclin D1 (CCND1) and cortactin (CTTN) in oral carcinoma and oral brushed samples from areca chewers

Oral squamous cell carcinoma (OSCC) in Asians is highly associated with the abuse of areca (betel) chewing. There are several hundred million Asians who chew areca and are therefore at high risk of OSCC. Aberrance in cyclin D1 (CCND1) and/or cortactin (CTTN), which are localized on 11q13, seems to be critical events for the development of oral carcinogenesis. This study identified amplifications of CCND1 and CTTN by quantitative (Q)-PCR analysis in 50% and 45% of OSCC samples, respectively. Co-amplification of both genes was identified in 20% of tumors. Higher CTTN expression was associated with nodal metastasis of the OSCC, while the amplification of CCND1 was identified in 28% of oral brushed samples from areca chewers, who form a high risk group for OSCC. This study confirms the importance of alterations in CCND1 and CTTN with respect to areca-associated OSCC, and demonstrates that there is an early occurrence of amplification of these genes in the risk population. The non-invasive brushing sampling method coupling with Q-PCR analysis needs to be validated for use as an early detection system for gene copy changes, which should aid oral cancer prevention.

K14-EGFP-miR-31 transgenic mice have high susceptibility to chemical-induced squamous cell tumorigenesis that is associating with Ku80 repression.

Squamous cell carcinoma (SCC) occurring in the head and neck region and the esophagus causes tremendous cancer mortality around the world. miR‐31 is among the most eminently upregulated MicroRNAs in SCC, when it occurs in the head and neck region and the esophagus. We established miR‐31 transgenic mouse lines, in which miR‐31 is under the control of the K14 promoter. 4‐nitroquinoline 1‐oxide (4NQO) is a mutagen that causes double strand breaks. The transgenic mice exhibited a higher potential for tumor induction than wild‐type (Wt) mice of the tongue and esophagus after 4NQO treatment. After 4NQO treatment or irradiation, p‐γH2AX expression in squamous epithelium of transgenic mice was increased more than in Wt mice. Exogenous expression of miR‐31 was also found to be associated with the higher p‐γH2AX expression induced by 4NQO in human oral SCC (OSCC) cell lines. The repair genes PARP1 and Ku80 were validated as new targets of miR‐31 in human OSCC cell lines, and were found to be downregulated in the squamous epithelium of the tongue in transgenic mice. However, only the downregulation of Ku80 was essential for maintaining the high level of p‐γH2AX induced by 4NQO in OSCC cells. Inverse expression profiles for miR‐31 and Ku80 were noted in human OSCC tissue. Our study identifies the high sensitivity of K14‐EGFP‐miR‐31 transgenic mice to chemical carcinogen‐induced squamous cell tumorigenesis and shows that this seems to be associated with the downregulation of Ku80 and an impairment of repair activity in squamous cells, which are mediated by miR‐31.

Serum decoy receptor 3 level: A predictive marker for nodal metastasis and survival among oral cavity cancer patients

Validating markers for prediction of nodal metastasis could be beneficial in treatment of oral cavity cancer. Decoy receptor 3 (DcR3), locus on 20q13, functions as a death decoy inhibiting apoptosis mediated by the tumor necrosis factor receptor (TNFR) family.

The frequent co-expression of the oncogenes PIK3CA and PAK1 in oral carcinomas

PIK3CA and PAK1 are critical genes in the PI3K/AKT/PAK pathway. Amplification and strong expression of PIK3CA and PAK1 were identified in around 50% and 88% oral carcinomas, respectively, while co-expression of PIK3CA and PAK1 together was found to be present in 80% of oral carcinomas. PIK3CA and PAK1 amplification was more obvious in recurrent tumors than their primary counterparts. Low grade amplification of PAK1 was prevalent in tumor risk individuals. Knockdown of expression of PIK3CA and PAK1 reduced the oncogenic potential of tumor cells. This study is the first to demonstrate the concordant PIK3CA and PAK1 alterations in oral carcinoma.

Up-regulation of miR-187 modulates the advances of oral carcinoma by targeting BARX2 tumor suppressor

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Aberrations in miRNA regulation are known to play important roles in OSCC pathogenesis. miR-187 was shown to be up-regulated in head and neck malignancies in our previous screening. This study further investigated the oncogenic potential, clinical implications, and targets of miR-187 in OSCC. We observed that miR-187 increased oncogenicity, particularly migration, of OSCC cells. miR-187 expression increased the xenografic tumorigenicity and metastasis in mice. In addition, metastatic human OSCC had higher miR-187 expression than did non-metastatic tumors. Through vigorous screening, we confirmed BarH-like Homeobox 2 (BARX2) gene as an miR-187 target. BARX2 expression suppressed the migration, invasion, anchorage-independent colony formation, and orthotopic tumorigenesis of OSCC cells. The migratory phenotype and neck metastasis induced by miR-187 was rescued by BARX2 expression. BARX2 expression was down-regulated in the vast majority of OSCC, and this down-regulation was particularly conspicuous in tumors with advanced nodal metastasis. In addition, plasma miR-187 was significantly higher in OSCC patients than in normal individuals. This study highlights the roles of miR-187-BARX2 in driving the carcinogenesis of OSCC. The results suggest that miR-187 is a potential serological marker for OSCC and that targeting of miR-187 might prove effective in attenuating nodal metastasis.

MicroRNA-21 promotes perineural invasion and impacts survival in patients with oral carcinoma

Background Perineural invasion is a pathological feature that may affect cancer cell progression and thus can result in prognostic impacts, especially in oral squamous cell carcinoma (OSCC). However, factors regulating perineural invasion during OSCC remain obscure. Methods Expression of miR‐21 and phosphatase and tensin homolog was checked in surgical specimens from cases of OSCC. The results were analyzed for histopathologic factors, including perineural invasion and clinical prognosis. Results One‐hundred cases of OSCC patients were enrolled in this study. High expression of miR‐21 was related to perineural invasion and worse prognosis in OSCC patients. Conclusion miR‐21 was an independent factor of disease survival of OSCC. miR‐21/phosphatase and tensin homolog disregulation was related to perineural invasion.

Implant Rehabilitation of Severely Traumatised Anterior Alveolar Ridge

Abstract Objective: To propose a sequential treatment approach for implant rehabilitation of a traumatised and deficient maxillary or mandibular alveolar ridge. Patients and Methods: Patients with severely deficient alveolar ridge and loss of teeth due to injury underwent sequential reconstructive procedures at the maxillary or mandibular edentulous areas with autogenous symphyseal bone or allogeneic bone graft with guided bone regeneration; vestibuloplasty with or without keratinised palatal mucosal graft to rebuild the vestibule; and implant rehabilitation. Postoperative followup consisted of clinical and radiographic examinations. Results: Thirty six implant fixtures were placed in the maxilla or mandible in 12 patients. The average follow-up period after treatment was 4 years. Before surgery, all patients had severely deficient ridges with a compromised shallow vestibule. Satisfactory results were observed in regard to the long-term stability of the rehabilitation result, contour of the reconstructed ridge, morphology of the vestibule, health of the periimplant tissue, and functionality of the implant-retained prostheses. Conclusion: The proposed sequential reconstructive treatment approach for both hard and soft tissues offers a reliable method of implant rehabilitation after traumatic injury.

Cervical Vertebrae Metastases in Oral Squamous Cell Carcinoma: A Case Report

Cervical vertebrae metastases is rare in oral squamous cell carcinoma (OSCC). Due to the improvement of locoregional control in advanced OSCC by the advancement of treatment modality, more patients are faced with the risk of developing distant metastases. The lung, skeleton and liver are the most frequent sites of distant metastases in OSCC. Vertebrae metastases is relatively rare, and the most frequent site of vertebrae metastases is thoracic vertebrae, followed by lumbar vertebrae. In this article, a case of advanced OSCC who received local wide excision ± neck dissection and adjuvant concurrent chemo-radiotherapy with cervical vertebrae metastases is reported. A literature review on the diagnosis, possible mechanism, therapeutic modalities and prognosis is mentioned in this article.