Retinoic acid receptor-alpha as a prognostic indicator in oral squamous cell carcinoma

Retinoids reverse potentially malignant lesions and inhibit the development of second primary tumors in oral cancer patients by binding to nuclear retinoid receptors. Alterations in the expression of retinoid receptor-alpha are implicated in tumor progression. Herein, we hypothesized that increased expression of RARalpha protein in oral squamous cell carcinoma (SCC) is associated with a poor clinical outcome and thus may serve as a prognostic factor. Retrospective immunohistochemical analysis of RARalpha protein expression was carried out in paraffin-embedded tissue sections from 115 patients with completely resected oral SCCs for whom clinical follow-up data were available. Increased expression of RARalpha protein was observed in 67/115 (58%) oral SCCs (weakly positive in 38 patients and strongly positive in 29 patients). Kaplan-Meier analysis showed that patients with RARalpha positivity had significantly shorter disease-free survival time (median time 40 months vs. 86 months, p = 0.0229). Furthermore, disease-free survival time of the 29 patients with strongly positive RARalpha was significantly worse than for the 86 patients with weak or undetectable levels of RARalpha (p = 0.0328). Strong RARalpha expression in oral SCCs was associated with a significantly worse disease-free survival, suggesting that RARalpha may serve as a prognostic indicator of poor clinical outcome. Further studies are warranted to determine its utility in identifying the subset of patients who would benefit from use of retinoids as adjuvant in chemotherapy or chemopreventive approaches.     

MGMT expression in oral precancerous and cancerous lesions: correlation with progression, nodal metastasis and poor prognosis

Alkylation of DNA at the O(6) position of guanine is a critical step in the induction of mutations by carcinogenic and chemotherapeutic alkylating agents. O(6)-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes mutagenic adducts from the O(6) position of guanine, thereby protecting the genome against guanine to adenine transitions. We hypothesized that alteration in MGMT expression might occur in early stages of development of oral cancer and be associated with disease progression. Immunohistochemical analysis of MGMT expression was carried out in 107 oral squamous cell carcinomas (OSCCs), 78 oral precancerous lesions (OPLs) (58 hyperplasias and 20 dysplasias) and 30 histologically normal oral tissues and correlated with clinicopathological parameters as well as major risk factors. Decreased MGMT expression was observed as early as in hyperplasia (p=0.003; Odd's Ratio (OR)=5.0). Significant loss of MGMT expression was observed from hyperplasia to dysplasia (p=0.034; OR=4.0). Loss of MGMT expression was associated with late clinical stage of OSCCs (p=0.027, OR=2.0) and nodal metastasis (p=0.031, OR=2.5). Decreased MGMT expression was associated with smokeless tobacco (ST) consumption in patients with OPLs (p=0.017, OR=3.6) and OSCCs (p=0.031, OR=2.8). Significant association was also observed between loss of MGMT expression and poor prognosis of OSCC patients (p=0.02; OR=5.2). The decreased MGMT expression in OPLs suggested that deregulation of MGMT expression is an early event in the development of oral cancer. In OSCCs, its correlation with late clinical stage, and nodal metastasis suggests association with aggressive tumor behavior and cancer progression, underscoring its potential as a candidate predictive marker for nodal metastasis and disease prognosis. Correlation of loss of MGMT expression with ST consumption underscored its significance in ST-associated oral carcinogenesis.     

Prognostic significance of nm23-H1 expression in oral squamous cell carcinoma

Recent studies indicated nm23-H1 played a role in cancer progression. Therefore, we investigated clinical significance of nm23-H1 expression in oral squamous cell carcinoma (OSCC). In total, 86 OSCC specimens were immunohistochemically stained with nm23-H1-specific monoclonal antibodies. Immunohistochemical staining of nm23-H1 was confirmed by immunoblotting. The relations between nm23-H1 expression and clinicopathologic variables were evaluated by chi(2) analysis. As increased size of primary tumour could escalate metastatic potential and the data of patients at the late T stage might confound statistical analyses, we thus paid special attention to 54 patients at the early T stage of OSCC. Statistical difference of survival was compared by a log-rank test. Immunohistochemically, nm23-H1 expression was detected in 48.8% (42 out of 86) of tumorous specimens. It positively correlated with larger primary tumour size (P=0.03) and inversely with cigarette-smoking habit (P=0.042). In patients at the early T stage, decreased nm23 expression was associated with increased incidence of lymph node metastasis (P=0.004) and indicated poor survival (P=0.014). Tumour nm23-H1 expression is a prognostic factor for predicting better survival in OSCC patients at the early T stage, which may reflect antimetastatic potential of nm23. Therefore, modulation of nm23-H1 expression in cancer cells can provide a novel possibility of improving therapeutic strategy at this stage. In addition, our results further indicated cigarette smoking could aggravate the extent of nm23-H1 expression and possibly disease progression of OSCC patients.     

HMGB1蛋白在口腔鳞癌组织中的表达及其与患者预后的关系

目的:探讨口腔鳞癌(OSCC)组织中高迁移率族蛋白1(HMGB1)蛋白的表达情况,并分析其与临床病理特征及预后的关系.方法:采用免疫组织化学SP法分别检测HMGB1在126例OSCC组织和30例正常口腔黏膜组织中的表达;分析HMGB1表达情况与OSCC临床病理特征的关系;Kaplan-Meier法分析HMGB1蛋白表达...     

Convergent dysbiosis of upper aerodigestive microbiota between patients with esophageal and oral cavity squamous cell carcinoma

The bidirectional association between primary esophageal squamous cell carcinoma (ESCC) and oral cavity squamous cell carcinoma (OSCC) suggests common risk factors and oncogenic molecular processes but it is unclear whether these two cancers display similar patterns of dysbiosis in their upper aerodigestive microbiota (UADM). We conducted a case-control study to characterize the microbial communities in esophageal lavage samples from 49 ESCC patients and oral rinse samples from 91 OSCC patients using 16S rRNA V3-V4 amplicon sequencing. Compared with their respective non-SCC controls from the same anatomical sites, 32 and 45 discriminative bacterial genera were detected in ESCC and OSCC patients, respectively. Interestingly, 20 of them were commonly enriched or depleted in both types of cancer, suggesting a convergent niche adaptation of upper aerodigestive SCC-associated bacteria that may play important roles in the pathogenesis of malignancies. Notably, Fusobacterium, Selenomonas, Peptoanaerobacter and Peptostreptococcus were enriched in both ESCC and OSCC, whereas Streptococcus and Granulicatelia were commonly depleted. We further identified Fusobacterium nucleatum as the most abundant species enriched in the upper aerodigestive SCC microenvironment, and the higher relative abundances of Selenomonas danae and Treponema maroon were positively correlated with smoking. In addition, predicted functional analysis revealed several depleted (eg, lipoic acid and pyruvate metabolism) and enriched (eg, RNA polymerase and nucleotide excision repair) pathways common to both cancers. Our findings reveal a convergent dysbiosis in the UADM between patients with ESCC and OSCC, suggesting a shared niche adaptation of host-microbiota interactions in the pathogenesis of upper aerodigestive tract malignancies.     

miR-31和miR-1322在口腔鳞癌中的表达及与细胞增殖的关系

目的:检测微小RNA-31(microRNA-31,miR-31)和微小RNA-1322(microRNA-1322,miR-1322)在口腔鳞癌中的表达特征,分析其临床意义,探讨其与细胞增殖的关系。方法:选取2013年1月至2013年12月我院收治的75例口腔鳞癌患者为研究对象,选取肿瘤组织作为观察组,选取距肿物边缘>3 cm的正常口腔鳞状上皮组织作为对照组,应用实时荧光定量PCR法检测两组中miR-31和miR-1322的表达,应用免疫组化方法检测肿瘤组织中Ki67表达的增殖指数。结果:观察组中miR-31和miR-1322的表达明显高于对照组,观察组中miR-31和miR-1322的表达在不同分化程度、肿物最大径、淋巴结转移及TNM分期的表达中差异有统计学意义。生存分析显示二者的表达与生存时间相关。相关分析显示观察组中miR-31和miR-1322的表达均与增殖指数呈正相关性。结论:口腔鳞癌中miR-31和miR-1322高表达是肿瘤形成的促进因素。miR-31和miR-1322均对细胞增殖有促进作用,检测组织miR-31和miR-1322的表达对判断预后可能有一定价值。     

Rose bengal staining in detection of oral precancerous and malignant lesions with colorimetric evaluation: a pilot study

Early detection of oral precancerous and malignant lesions is still a diagnostic challenge for most of clinicians, and ideal adjuncts for detection of these lesions are currently unavailable. Our preliminary study has indicated that rose bengal (RB) staining might have the potency as a diagnostic aid; however, its clinical significance and reliability in hospital-based population are still not clear. In the present study, we investigated the efficacy of RB staining in detection of oral precancerous and malignant lesions. RB staining was conducted in 132 patients, and staining results were determined by a 4-graded shade guide, which had been quantitatively measured in the 1976 CIEL*a*b* space by instrumental colorimetry. Histological examination was performed in 128 of 132 patients after RB staining. The sensitivity and specificity to detect epithelial dysplasia (DP) and oral squamous cell carcinoma were 93.9 and 73.7%, respectively. The positive and negative likelihood ratios were 3.570 and 0.082, respectively. Moreover, RB staining seemed promising to detect DP in oral leukoplakia, lichen planus and leukokeratosis. In this study, 5 of 6 DP or oral squamous cell carcinoma were identified by RB staining before histological examination. In conclusion, RB staining may be a valuable diagnostic test in detection of oral precancerous and malignant lesions.     

细胞周期调控因子在胃癌组织中的表达及意义

背景与目的细胞周期调控异常与细胞过度增殖及肿瘤发生密切相关,而细胞周期调控因子与胃癌的关系尚未明确。本研究目的是探讨细胞周期调控因子P16INK4、CyclinD1、P21WAF1、P53在胃癌组织中的表达及意义。方法运用免疫组织化学SP法检测53例胃癌及癌旁组织中细胞周期调控因子P16INK4、CyclinD1、P21WAF1、P53的表达。采用多变量Cox回归模型对影响预后的因素进行分析。结果P53蛋白在胃癌组织中的阳性率为60.4%,显著高于癌旁组织(0%)(P<0.01);P53蛋白表达在粘液癌(0%)与高分化腺癌(65.4%)和低分化腺癌(68.2%)间有显著性差异(P<0.01)。CyclinD1蛋白在胃癌组织中的过表达率为69.8%,显著高于癌旁组织(5.7%)(P<0.01)。P16INK4蛋白在胃癌组织中的阳性率为60.3%,显著低于癌旁组织(88.6%)(P<0.05)。P21WAF1蛋白在胃癌组织中的阳性率为26.4%,显著低于癌旁组织(56.6%)(P<0.01)。P16INK4表达与胃癌浸润深度及淋巴结转移相关(分别为P<0.05,P<0.01)。多因素Cox回归分析表明,淋巴结转移、P16INK4为独立预后因素。结论P16INK4蛋白、P21WAF1蛋白低表达和CyclinD1蛋白、P53过度表达与胃癌发生发展有关;P16INK4蛋白的低表达与胃癌浸润、转移及预后有一定关系。     

新辅助化疗在老年中晚期口腔鳞状细胞癌治疗中的临床意义

目的：探讨分析新辅助化疗在治疗老年中晚期口腔鳞状细胞癌中的临床效果。方法收集46例老年中晚期口腔鳞状细胞癌行新辅助化疗患者作为研究组,选取同期收治的60例未行新辅助化疗老年中晚期口腔鳞状细胞癌患者作为对照组,统计入组患者新辅助化疗后临床有效率、病理有效率,对比新辅助化疗前后细胞凋亡及增殖指数,肿瘤组织Ki-67、EGFR、p53及RARβ的表达变化,并分析新辅助化疗后手术及生存情况,比较两组生存率差异。结果研究组化疗后临床有效率和病理有效率分别为80.43%和69.57%。化疗后细胞凋亡指数明显高于化疗前,细胞增殖指数低于化疗前,差异均具有统计学意义（P=0.007、0.015）。化疗后Ki-67、EGFR、p53均低于化疗前,RARβ高于化疗前,差异均具有统计学意义（P=0.004、0.027、0.021、0.013）。研究组患者的中位生存期为28个月,新辅助化疗3、4个疗程患者远期生存率高于2个疗程患者,差异有统计学意义（P=0.021、0.017）。3个疗程和4个疗程化疗患者远期生存率比较差异无统计学意义（P=0.117）。对照组患者中位生存期为17个月,两组患者生存率差异具有统计学意义（P=0.015）。结论新辅助化疗可从多方面改善老年中晚期口腔鳞状细胞癌的临床效果,应成为其综合治疗的重要组成部分。     

ras蛋白在食管癌及食管癌前病变组织中的表达

目的了解中国食管癌高发区食管癌变发生过程中癌基因ｒａｓ的变化。方法采用卵白素－生物素－辣根过氧化氢酶复合物（ＡＢＣ）方法测定食管癌高发区食管癌及癌前病变组织中癌基因ｒａｓ蛋白的表达状况。结果在正常食管上皮和癌前病变组织中未见ｒａｓ蛋白表达,而３６例食管癌组织有９例出现免疫阳性反应,其免疫阳性反应率为２５％。结论ｒａｓ癌基因表达是食管癌变晚期阶段的一个分子学变化。     

Expression of cyclooxygenase-2 and DNA topoisomerase II alpha in precancerous and cancerous lesions of the oral mucosa

The involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and outcome of the patients is not fully understood. To determine whether COX-2 expression could serve as an indicator for them, we examined the expression of COX-2 and DNA topoisomerase (DNA-Topo) II alpha as an index of cell proliferating activity in precancerous and cancerous lesions of the oral mucosa. A 164 samples composed of 60 intraepithelial dysplasias (IEDs), 12 carcinomas in situ (CISs), 72 squamous cell carcinomas (SCCs) including 12 early invasive SCCs, 10 undifferentiated carcinomas (UCs), and 10 epithelial hyperplasias (EHPs) in the oral mucosa were examined immunohistochemically for COX-2 and DNA-Topo II alpha. Normal squamous epithelium as the control showed no COX-2 expression, whereas 41% of IEDs, 67% of CISs, 74% of SCCs, and 86% of UCs demonstrated increased COX-2 expression with elevated DNA-Topo II alpha labeling index (LI). High COX-2 expression was also observed in 61% of EHPs, but DNA-Topo II alpha LI was very low. Increased expression of COX-2 protein correlated with elevated DNA-Topo II alpha LI, indicating that COX-2 may contribute to malignant transformation and tumor growth. These two enzyme activities were increased as T, N, and M categories and stages proceeded. The patients with high expression of both COX-2 and DNA-Topo II alpha showed poor prognosis. Our results suggested that COX-2 expression become a possible indicator in oral carcinogenesis and may reflect the outcome of the patients.     

Heteromorphisms of C-bands in patients with precancerous and cancerous lesions of the cervix uteri

C-band heteromorphisms of chromosomes 1, 9 and 16 were studied in 62 patients with cervical cancer, 100 women with various grades of precancerous lesions and 47 normal women as controls. The data showed an increased frequency of heteromorphisms of chromosome 1 in patients with cancer (48.39%) and severe dysplasias (40%) as compared to controls (29.8%) and lower grades of dysplastic lesions, i.e. mild and moderate (28.8%). The increase in the incidence of chromosome 1 heteromorphisms in cancer was found to be statistically significant (p less than 0.05) compared to controls. The present study indicates that C-band heteromorphisms may play some role in the development of malignancy of the uterine cervix.     

人类端粒酶RNA和C-myc基因在子宫颈癌及癌前病变组织中的表达及其临床意义

目的探讨人类端粒酶RNA（hTERC）及原癌基因C—myc在子宫颈病变中的表达。方法荧光原位杂交（FISH）法检测35例子宫颈上皮内瘤样病变（CIN）、8例浸润性子宫颈癌、19例炎性反应（对照）患者子宫颈组织中hTERC和C-myc基因的表达情况。结果3号染色体上的hTERC基因在慢性子宫颈炎组织、CINⅠ、CINⅡ～Ⅲ及子宫颈癌中的阳性率分别为5．3％（1／19）、16．7％（2／12）、87．0％（20／23）及87．5％（7／8）,CINⅡ～Ⅲ及子宫颈癌中阳性率明显升高（χ^2=36．299,P〈0．01;χ^2=40．237,P〈0．01）,原癌基因C-myc阳性率分别为5．3％（1／19）、8．3％（1／12）、78．3％（18／23）及62．5％（5／8）,CINⅡ-Ⅲ及子宫颈癌中阳性率明显升高（χ^2=30．200,P〈0．01;χ^2=34．224,P〈0．01）。CINⅡ～Ⅲ及子宫颈癌中hTERC和C—myc基因表达之间呈正相关（r=0．514,P〈0．01）。结论3号染色体上hTERC基因及原癌基因C-myc的阳性表达与子宫颈癌的发生、发展可能有密切关系。     

EXPRESSION OF THE RETINOIC ACID RECEPTORS(RARs)AND RETINOID X RECEPTOR(RXRs)GENES IN BREAST CANCER

A number of studies have been shown that retiniodscan inhibit malignant cell growth including certain breastcarcinoma cells. its inhibitory effort is observed only inER-positive but not in ER-negative breast cancer cells.We examined retinoic acid receptors (RARs) andretinoids X receptors(RXRs) levels in 6 breast carcinomacell lines and 18 breast cancer biopsy specimens. Wefound that RAR-α mRNA level was significantly higher inER Positive cell lines and samples. RAR-γ mRNA wasexpressed at relatively high levels in majority of tumorsamples independent of the ER-status while RAR-βmRNA was expressed at low levels. We also found highRXR-α mRNA levels in all of the tumor samplesexamined while RXR-γ mRNA could not be detected.Our study suggests a possibility that retinoids inhibittumor cell growth through RAR-α and RAR-α levels mayserve as a potential marker to determine responsivenessof patients to retinoids therapy.     

MicroRNA-625 在食管鳞癌中的表达及临床意义*

目的:探讨microRNA- 625（miR-625）在食管鳞癌（esophageal squamous cell carcinoma ,ESCC）中的表达及其与临床参数的相关性,探究miR-625 对ESCC细胞系KYSE70迁移和增殖的影响。方法:实时荧光定量（real-time polymerase chain reaction ,PCR ）检测2014年2 月至2015年4 月郑州大学第一附属医院手术切除的86例ESCC及癌旁正常组织、ESCC细胞系和正常永生化食管上皮细胞系中miR-625 的表达,统计学分析其表达水平与ESCC患者临床病理参数及预后的相关性。Transwell 实验检测miR-625 对细胞迁移能力的影响,细胞计数Kit- 8（CCK-8）法检测miR-625 对细胞增殖的影响。结果:ESCC组织中miR-625 的表达明显低于癌旁正常组织（P < 0.05）,ESCC细胞系中miR-625 表达水平与正常永生化食管上皮细胞相比,显著下调（P < 0.05）。miR-625 的表达与肿瘤直径、分化程度及淋巴结转移呈负相关（P < 0.05）。 随访数据提示miR-625 低表达组患者预后更差（P <0.05）。 miR-625 能够抑制ESCC的迁移和增殖（P < 0.05）。 结论:miR-625 作为抑癌基因参与ESCC的发生发展,提示miR-625 可能作为一个ESCC治疗靶点和预后判断的分子标志物。      

Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma

BACKGROUND: The objective of this study was to compare survival in patients with squamous cell carcinoma (SCC) of the oral tongue with that in patients with SCC in other oral cavity subsites. METHODS: Patients with stage I and II (T1-T2N0M0) SCC of the oral cavity diagnosed between 1988 and 2004 were queried by using the Surveillance, Epidemiology, and End Results (SEER) database. The log-rank test was used to compare the overall survival (OS) and cause-specific survival (CSS) of patients who had oral tongue SCC with those of patients who had SCC of other oral cavity subsites. A Cox proportional hazards multivariate analysis was performed to evaluate the influence of covariates on the risk of CSS and OS. RESULTS: Between 1988 and 2004, 6791 patients with stage I and II SCC of the oral cavity were identified. Among them, 40% had oral tongue SCC, and 60% had SCC of other oral cavity subsites. The median patient age was 64 years. The 5-year OS and CSS rates were 60.9% and 83.5%, respectively, for patients with oral tongue SCC versus 64.7% and 94.1%, respectively, for patients with SCC of other oral cavity subsites (OS: hazard ratio, 1.24; P< .0001; CSS: hazard ratio, 3.04; P< .0001). On multivariate analysis, OS and CSS were influenced significantly by T classification, age, sex, and oral tongue subsite. The CSS for patients who had stage I and II oral tongue SCC also was unfavorable compared with the CSS for stage-matched patients who had SCC of other head and neck sites. CONCLUSIONS: Oral tongue SCC was associated with poor survival compared with other oral cavity and head and neck sites. These data suggested a potential benefit for multimodality therapy in this cohort of patients.