MMP-14和缺氧诱导因子-1α在口腔鳞癌组织中表达及临床意义
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摘要
目的探讨口腔鳞癌(OSCC)组织中基质金属蛋白酶-14(MMP-14)和缺氧诱导因子-1α(HIF-1α)的表达及其临床意义,为临床诊治OSCC提供依据。方法选择经病理组织确诊OSCC患者80例,其中男性45例,女性35例;年龄35~77岁,平均年龄52.85岁;根据TNM分期标准,其中Ⅰ期15例,Ⅱ期23例,Ⅲ期26例,Ⅳ期16例;分化程度,低分化45例,中分化23例,高分化12例。20例活组织检查正常口腔黏膜组织作为对照组,其中男性11例,女性9例;年龄33~68岁,平均年龄52.17岁。应用免疫组织化学的链霉素抗生物素蛋白-过氧化物酶(SP)法检测80例OSCC组织(OSCC组)、80例OSCC癌旁组织(癌旁组)、正常口腔黏膜组织20例(正常组)中MMP-14和HIF-1α的表达阳性率。分析癌组织中MMP-14和HIF-1α表达与OSCC转移、分期及预后的关系。采用Spearman相关分析法分析MMP-14和HIF-1α表达的相关性。结果 OSCC组MMP-14和HIF-1α表达阳性率明显高于癌旁组和正常组(83.75%vs 28.75%vs 5.00%、88.75%vs 23.75%vs 5.00%;P_(MMP-14)=0.000、0.000、0.012,P_(HIF-1α)=0.000、0.011、0.024)。有淋巴结转移的患者癌组织中MMP-14和HIF-1α表达阳性率明显高于无淋巴结转移患者(94.55%vs 60.00%,96.36%vs 72.00%;P_(MMP-14)=0.016,PHIF-1α=0.002);Ⅰ+Ⅱ期患者癌组织MMP-14和HIF-1α表达阳性率明显低于Ⅲ+Ⅳ期(68.42%vs 97.65%,78.95%vs 97.62%;P_(MMP-14)=0.009,PHIF-1α=0.008);MMP-14和HIF-1α表达呈正相关关系(r=0.713,P=0.024);MMP-14阴性表达患者总生存率与MMP-14表达(+)、(++)及(+++)患者总生存率比较,差异有统计学意义(P=0.021、0.022、0.000);HIF-1α阴性表达患者总生存率与HIF-1α表达(+)、(++)及(+++)患者总生存率比较,差异有统计学意义(P=0.011、0.012、0.001)。结论 MMP-14和HIF-1α异常表达与OSCC的发生、发展密切相关,其表达上调参与肿瘤形成、发展、侵袭和转移,可作为判断OSCC生物学行为的临床参考指标。
Objective To investigate the expressions of matrix metalloproteinase 14(MMP-14) and hypoxia-inducible factor 1α(HIF-1α) in oral squamous cell carcinoma(OSCC) tissue and the clinical significance, and provide basis for diagnosis and treatment. Methods A total of 80 OSCC patients confirmed by pathological test were enrolled, which included 45 males and35 females, aged 35-77 years old with mean age of 52.85 years old. According to TNM staging criteria, 15 cases were stageⅠ, 23 of stage Ⅱ, 26 of stage Ⅲ and 16 of stage Ⅳ. According to differentiation stage, 45 cases were low differentiation, 23 of middle differentiation and 12 of high differentiation. Twenty cases of normal oral mucosa were select in control group, which included 11 males and 9 females, aged 33-68 years old with mean age of 52.17 years old. Positive expression rates of MMP-14 and HIF-1α in OSCC group(80 cases of OSCC), adjacent group(80 of OSCC adjacent tissue) and normal group(20 of normal oral mucosa) were detected by immunohistochemical streptomycin avidin-capsidase(SP) assay. The correlation expressions between MMP-14 and HIF-1α were analyzed by Spearman correlation analysis method. Results The positive expression rates of HIF-1α and MMP-14 in OSCC group were obviously higher than those in adjacent group and normal group(83.75 % vs28.75 % vs 5.00 %, 88.75 % vs 23.75 % vs 5.00 %; P_(MMP-14)= 0.000, 0.000, 0.012, PHIF-1α= 0.000, 0.011, 0.024). The positive expression rates of HIF-1α and MMP-14 expression in patients with lymph node metastasis were significantly higher than those without lymph node metastasis(94.55 % vs 60.00 %, 96.36 % vs 72.00 %; P_(MMP-14)= 0.016, P_(HIF-1α)= 0.002). The positive expression rates of MMP-14 and HIF-1α in cancer tissues of patients with stage Ⅰ + Ⅱ were significantly less than those with stage Ⅲ + Ⅳ(68.40 % vs 97.62 %, 78.95 % vs 97.62 %; P_(MMP-14)= 0.009, PHIF-1α= 0.008). There was a positive correlation between MMP-14 and HIF-1α expression(r = 0.713, P = 0.024); The differences of overall survival rate between MMP-14 expression negative patients and MMP-14 expression(+),(++) and(+++) were statistically significant(P = 0.021, 0.022, 0.000).The patient's overall survival rate of negative HIF-1α expression group was significantly higher than that of HIF-1α expression(+),(++) and(+++)(P = 0.011, 0.012, 0.001). Conclusion It is demonstrated that the abnormal expression of MMP-14 and HIF-1α is closely related to the occurrence and development of OSCC, which involved in tumor formation, development, invasion and metastasis. It could be used as a clinical reference index to assess OSCC biological behavior.
Objective To investigate the expressions of matrix metalloproteinase 14(MMP-14) and hypoxia-inducible factor 1α(HIF-1α) in oral squamous cell carcinoma(OSCC) tissue and the clinical significance, and provide basis for diagnosis and treatment. Methods A total of 80 OSCC patients confirmed by pathological test were enrolled, which included 45 males and35 females, aged 35-77 years old with mean age of 52.85 years old. According to TNM staging criteria, 15 cases were stageⅠ, 23 of stage Ⅱ, 26 of stage Ⅲ and 16 of stage Ⅳ. According to differentiation stage, 45 cases were low differentiation, 23 of middle differentiation and 12 of high differentiation. Twenty cases of normal oral mucosa were select in control group, which included 11 males and 9 females, aged 33-68 years old with mean age of 52.17 years old. Positive expression rates of MMP-14 and HIF-1α in OSCC group(80 cases of OSCC), adjacent group(80 of OSCC adjacent tissue) and normal group(20 of normal oral mucosa) were detected by immunohistochemical streptomycin avidin-capsidase(SP) assay. The correlation expressions between MMP-14 and HIF-1α were analyzed by Spearman correlation analysis method. Results The positive expression rates of HIF-1α and MMP-14 in OSCC group were obviously higher than those in adjacent group and normal group(83.75 % vs28.75 % vs 5.00 %, 88.75 % vs 23.75 % vs 5.00 %; P_(MMP-14)= 0.000, 0.000, 0.012, PHIF-1α= 0.000, 0.011, 0.024). The positive expression rates of HIF-1α and MMP-14 expression in patients with lymph node metastasis were significantly higher than those without lymph node metastasis(94.55 % vs 60.00 %, 96.36 % vs 72.00 %; P_(MMP-14)= 0.016, P_(HIF-1α)= 0.002). The positive expression rates of MMP-14 and HIF-1α in cancer tissues of patients with stage Ⅰ + Ⅱ were significantly less than those with stage Ⅲ + Ⅳ(68.40 % vs 97.62 %, 78.95 % vs 97.62 %; P_(MMP-14)= 0.009, PHIF-1α= 0.008). There was a positive correlation between MMP-14 and HIF-1α expression(r = 0.713, P = 0.024); The differences of overall survival rate between MMP-14 expression negative patients and MMP-14 expression(+),(++) and(+++) were statistically significant(P = 0.021, 0.022, 0.000).The patient's overall survival rate of negative HIF-1α expression group was significantly higher than that of HIF-1α expression(+),(++) and(+++)(P = 0.011, 0.012, 0.001). Conclusion It is demonstrated that the abnormal expression of MMP-14 and HIF-1α is closely related to the occurrence and development of OSCC, which involved in tumor formation, development, invasion and metastasis. It could be used as a clinical reference index to assess OSCC biological behavior.
引文
[1] Goertzen C, Mahdi H, Laliberte C, et al. Oral inflammation promotes oral squamous cell carcinoma invasion[J]. Oncotarget,2018, 9(49):29047-29063.
[2] Pramanik KK, Nagini S, Singh AK, et al. Glycogen synthase kinase-3βmediated regulation of matrix metalloproteinase-9and its involvement in oral squamous cell carcinoma progression and invasion[J]. Cell Oncol(Dordr), 2018, 41(1):47-60.
[3] LUO Xia, ZHOU Jing-xi, CHEN Hua-zhi. Study on relationship between HIF-1αand malignant transformation of oral leukoplakia[J]. China Modern Doctor, 2014, 52(5):28-30.[罗霞,周景喜,陈华志. HIF-1α与口腔白斑癌变的相关性研究[J].中国现代医生,2014,52(5):28-30.]
[4] Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer[J]. Int J Cancer, 2016, 138(5):1058-1066.
[5] Guimar觔es TA, Farias LC, Santos ES, et al. Metformin increases PDH and suppresses HIF-1αunder hypoxic conditions and induces cell death in oral squamous cell carcinoma[J].Oncotarget, 2016, 7(34):55057-55068.
[6] ZHANG Jin-hong, LIU Jun-ying, LIU Jian, et al. Expressions of FEZ1 and HIF-1αprotein in oral squamous cell carcinoma and its prognosis[J]. Tianjin Medicine, 2015, 43(11):1311-1314.[张晋弘,刘俊英,刘健,等.口腔鳞状细胞癌中FEZ1和HIF-1α蛋白表达及预后研究[J].天津医药,2015,43(11):1311-1314.]
[7] GUO Xing-huai, CHEN Jing-tian, HONG Han-lun, et al. The clinical relevance of MMP-14 and EMMPRIN expressing in oral squamous cell carcinoma[J]. Journal of Clinical Stomatology, 2017, 33(1):14-16, 17-17.[郭兴怀,陈敬天,洪汉伦,等. MMP-14与EMMPRIN在OSCC中的表达及临床意义[J].临床口腔医学杂志,2017,33(1):14-16,17-17.]
[8] ZHANG Yang-yang, REN Dong-hong, GONG Jian-zhuang.Effect and mechanism of matrix metalloprotease-14 expression on the migration and invasion of esophageal cancer cells[J]. Journal of Clinical Internal Medicine, 2018, 35(3):189-191.[张洋洋,任东红,公建庄.基质金属蛋白酶-14的表达对食管癌细胞迁移、侵袭能力的影响及其作用机制的研究[J].临床内科杂志,2018,35(3):189-191.]
[9] GAO Hao-ran, TONG De-hui, HUANG Ze-qing, et al. Expression and clinical significance of RECK, MMP-14 and VEGF protein in laryngeal carcinoma[J]. China Medical Hearld,2016, 13(2):85-88.[高浩然,佟德惠,黄泽清,等. RECK、MMP-14及VEGF在喉癌中的表达及临床意义[J].中国医药导报,2016,13(2):85-88.]
[10] MA Xin-fu, LIU Mei, GE Rui, et al. Expression of hypoxia inducible factor-1αand matrix metalloproteinase-14 in colon adenocarcinoma and their relationship with microvessel density[J]. Chinese Journal of Gerontology, 2017, 37(5):1164-1165.[马新福,刘梅,戈锐,等.结肠腺癌中缺氧诱导因子-1α和基质金属蛋白酶-14表达及与微血管密度的关系[J].中国老年学杂志,2017,37(5):1164-1165.]
[11] ZHOU Hai-ying, WU Ai-ping, LI Yan, et al. Expression levels and significance of semaphorin 3A and matrix metalloproteinase 14 in NSCLC[J]. Chinese Journal of Thoracic Cardiovascular Surgery, 2014, 30(9):550-553.[周海英,吴爱萍,李岩,等.信号素3A和基质金属蛋白酶-14在非小细胞肺癌中的表达及意义[J].中华胸心血管外科杂志,2014,30(9):550-553.]
[12] TAO Ye, ZHANG Ling-da. Expression and significance of MMP-14 and EMMPRIN in human oral squamous cell carcinoma[J]. Acta Universitatis Medicinalis Anhui, 2014, 49(1):81-84.[陶冶,张令达. MMP-14与EMMPRIN在口腔鳞状细胞癌中的表达及临床意义[J].安徽医科大学学报,2014,49(1):81-84.]
[13] TANG Xin-yi, ZHOU Hui. Expression levels and clinical significances of ALG-2, HIF-1αand VEGF in cancer tissues of oral squamous cell carcinoma[J]. Medical&Pharmaceutical Journal of Chinese People’s Liberation Army, 2017,29(3):42-45.[唐欣轶,周辉.口腔鳞癌组织中ALG-2、HIF-1α和VEGF的表达水平及临床意义[J].解放军医药杂志,2017,29(3):42-45.]
[14] Lee LT, Wong YK, Chan MY, et al. The correlation between HIF-1 alpha and VEGF in oral squamous cell carcinomas:Expression patterns and quantitative immunohistochemical analysis[J]. J Chin Med Assoc, 2018, 81(4):370-375.
[15] Tuomisto A, García-Solano J, Sirni觟P, et al. HIF-1αexpression and high microvessel density are characteristic features in serrated colorectal cancer[J]. Virchows Arch, 2016, 469(4):395-404.
[16] Kuo YY, Jim WT, Su LC, et al. Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer[J]. Int J MoI Sci, 2015, 16(5):10748-10766.
[17] Sun H, Miao C, Liu W, et al. TGF-β1/TβRII/Smad3 signaling pathway promotes VEGF expression in oral squamous cell carcinoma tumor-associated macrophages[J]. Biochem Biophys Res Commun, 2018, 497(2):583-590.
[18] Lin X, Li HR, Lin XF, et al. Silencing of Livin inhibits tumorigenesis and metastasis via VEGF and MMPs pathway in lung cancer[J]. Int J Oncol, 2015, 47(2):657-667.
[19] Han KY, Dugas-Ford J, Lee H, et al. MMP14 cleavage of VEGFR1 in the cornea leads to a VEGF-TRAP antiangiogenic effect[J]. Invest Ophthalmol Vis Sci, 2015, 56(9):5450-5456.
[2] Pramanik KK, Nagini S, Singh AK, et al. Glycogen synthase kinase-3βmediated regulation of matrix metalloproteinase-9and its involvement in oral squamous cell carcinoma progression and invasion[J]. Cell Oncol(Dordr), 2018, 41(1):47-60.
[3] LUO Xia, ZHOU Jing-xi, CHEN Hua-zhi. Study on relationship between HIF-1αand malignant transformation of oral leukoplakia[J]. China Modern Doctor, 2014, 52(5):28-30.[罗霞,周景喜,陈华志. HIF-1α与口腔白斑癌变的相关性研究[J].中国现代医生,2014,52(5):28-30.]
[4] Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer[J]. Int J Cancer, 2016, 138(5):1058-1066.
[5] Guimar觔es TA, Farias LC, Santos ES, et al. Metformin increases PDH and suppresses HIF-1αunder hypoxic conditions and induces cell death in oral squamous cell carcinoma[J].Oncotarget, 2016, 7(34):55057-55068.
[6] ZHANG Jin-hong, LIU Jun-ying, LIU Jian, et al. Expressions of FEZ1 and HIF-1αprotein in oral squamous cell carcinoma and its prognosis[J]. Tianjin Medicine, 2015, 43(11):1311-1314.[张晋弘,刘俊英,刘健,等.口腔鳞状细胞癌中FEZ1和HIF-1α蛋白表达及预后研究[J].天津医药,2015,43(11):1311-1314.]
[7] GUO Xing-huai, CHEN Jing-tian, HONG Han-lun, et al. The clinical relevance of MMP-14 and EMMPRIN expressing in oral squamous cell carcinoma[J]. Journal of Clinical Stomatology, 2017, 33(1):14-16, 17-17.[郭兴怀,陈敬天,洪汉伦,等. MMP-14与EMMPRIN在OSCC中的表达及临床意义[J].临床口腔医学杂志,2017,33(1):14-16,17-17.]
[8] ZHANG Yang-yang, REN Dong-hong, GONG Jian-zhuang.Effect and mechanism of matrix metalloprotease-14 expression on the migration and invasion of esophageal cancer cells[J]. Journal of Clinical Internal Medicine, 2018, 35(3):189-191.[张洋洋,任东红,公建庄.基质金属蛋白酶-14的表达对食管癌细胞迁移、侵袭能力的影响及其作用机制的研究[J].临床内科杂志,2018,35(3):189-191.]
[9] GAO Hao-ran, TONG De-hui, HUANG Ze-qing, et al. Expression and clinical significance of RECK, MMP-14 and VEGF protein in laryngeal carcinoma[J]. China Medical Hearld,2016, 13(2):85-88.[高浩然,佟德惠,黄泽清,等. RECK、MMP-14及VEGF在喉癌中的表达及临床意义[J].中国医药导报,2016,13(2):85-88.]
[10] MA Xin-fu, LIU Mei, GE Rui, et al. Expression of hypoxia inducible factor-1αand matrix metalloproteinase-14 in colon adenocarcinoma and their relationship with microvessel density[J]. Chinese Journal of Gerontology, 2017, 37(5):1164-1165.[马新福,刘梅,戈锐,等.结肠腺癌中缺氧诱导因子-1α和基质金属蛋白酶-14表达及与微血管密度的关系[J].中国老年学杂志,2017,37(5):1164-1165.]
[11] ZHOU Hai-ying, WU Ai-ping, LI Yan, et al. Expression levels and significance of semaphorin 3A and matrix metalloproteinase 14 in NSCLC[J]. Chinese Journal of Thoracic Cardiovascular Surgery, 2014, 30(9):550-553.[周海英,吴爱萍,李岩,等.信号素3A和基质金属蛋白酶-14在非小细胞肺癌中的表达及意义[J].中华胸心血管外科杂志,2014,30(9):550-553.]
[12] TAO Ye, ZHANG Ling-da. Expression and significance of MMP-14 and EMMPRIN in human oral squamous cell carcinoma[J]. Acta Universitatis Medicinalis Anhui, 2014, 49(1):81-84.[陶冶,张令达. MMP-14与EMMPRIN在口腔鳞状细胞癌中的表达及临床意义[J].安徽医科大学学报,2014,49(1):81-84.]
[13] TANG Xin-yi, ZHOU Hui. Expression levels and clinical significances of ALG-2, HIF-1αand VEGF in cancer tissues of oral squamous cell carcinoma[J]. Medical&Pharmaceutical Journal of Chinese People’s Liberation Army, 2017,29(3):42-45.[唐欣轶,周辉.口腔鳞癌组织中ALG-2、HIF-1α和VEGF的表达水平及临床意义[J].解放军医药杂志,2017,29(3):42-45.]
[14] Lee LT, Wong YK, Chan MY, et al. The correlation between HIF-1 alpha and VEGF in oral squamous cell carcinomas:Expression patterns and quantitative immunohistochemical analysis[J]. J Chin Med Assoc, 2018, 81(4):370-375.
[15] Tuomisto A, García-Solano J, Sirni觟P, et al. HIF-1αexpression and high microvessel density are characteristic features in serrated colorectal cancer[J]. Virchows Arch, 2016, 469(4):395-404.
[16] Kuo YY, Jim WT, Su LC, et al. Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer[J]. Int J MoI Sci, 2015, 16(5):10748-10766.
[17] Sun H, Miao C, Liu W, et al. TGF-β1/TβRII/Smad3 signaling pathway promotes VEGF expression in oral squamous cell carcinoma tumor-associated macrophages[J]. Biochem Biophys Res Commun, 2018, 497(2):583-590.
[18] Lin X, Li HR, Lin XF, et al. Silencing of Livin inhibits tumorigenesis and metastasis via VEGF and MMPs pathway in lung cancer[J]. Int J Oncol, 2015, 47(2):657-667.
[19] Han KY, Dugas-Ford J, Lee H, et al. MMP14 cleavage of VEGFR1 in the cornea leads to a VEGF-TRAP antiangiogenic effect[J]. Invest Ophthalmol Vis Sci, 2015, 56(9):5450-5456.