早期胃癌组织自噬相关基因LC3、Raptor、Rictor表达及意义
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摘要
目的探讨细胞自噬在胃癌发生中的作用及机制。方法选取正常胃黏膜、慢性萎缩性胃炎、低级别上皮内瘤变(LGIN)、高级别上皮内瘤变(HGIN)组织各30例份,早期胃癌组织40例份,分别记为正常组、胃炎组、LGIN组、HGIN组、胃癌组。采用免疫组化法检测各组自噬相关基因LC3、Raptor、Rictor表达,分析LC3、Raptor、Rictor表达的相关性以及早期胃癌组织LC3、Raptor、Rictor表达与患者临床病理参数的关系。结果正常组、胃炎组、LGIN组、HGIN组、胃癌组LC3表达逐渐升高,除LGIN组与胃炎组比较差异无统计学意义外,其他各组间比较差异均有统计学意义(P均<0.05)。Rictor在胃癌组、HGIN组、LGIN组表达均高于胃炎组和正常组(P均<0.05),胃癌组Raptor表达低于HGIN组、LGIN组(P均<0.05)。正常组、胃炎组、LGIN组、HGIN组、胃癌组Rictor表达逐渐升高,组间比较P均<0.05。LGIN组、HGIN组及胃癌组LC3表达与Raptor表达均呈负相关(r分别为-0.435、-0.168、-0.467,P均<0.05);LGIN组、HGIN组及胃癌组Raptor与Rictor表达均呈负相关(r分别为-0.260、-0.312、-0.223,P均<0.05)。早期胃癌组织LC3、Raptor与Rictor表达与肿瘤分化程度、浸润深度均相关(P均<0.05)。结论细胞自噬可促进胃癌的发生,其机制可能为促进LC3、Raptor、Rictor表达。LC3、Raptor、Rictor在促进胃癌的发生中起协同作用。
Objective To investigate the role and mechanism of autophagy in the gastric carcinogenesis.Methods We selected 30 cases of tissues from the normal gastric mucosa,chronic atrophic gastritis,low grade intraepithelial neoplasia( LGIN),and high grade intraepithelial neoplasia( HGIN),and 40 cases of early gastric cancer tissues,which were successively taken as the normal group,gastritis group,LGIN group,HGIN group,and gastric cancer group.The expression of LC3,Raptor,and Rictor of autophagy-related genes was detected by immunohistochemistry. The correlation of LC3,Raptor,and Rictor expression,and the relationship between the expression of LC3,Raptor,and Rictor in early gastric cancer and the clinicopathological parameters were analyzed. Results The expression of LC3 in the normal group,gastritis group,LGIN group,HGIN group,and gastric cancer group gradually increased. There was no significant difference between the LGIN group and the gastritis group,but there was a statistically significant difference among the other groups( all P < 0. 05). The Rictor expression in the gastric cancer group,HGIN group and LGIN group was higher than that in the gastritis group and normal group( P < 0. 05). The Raptor expression in the gastric cancer group was lower than that in the HGIN group and LGIN group( P < 0. 05). The expression of Rictor in the normal group,gastritis group,LGIN group,HGIN group,and the gastric cancer group gradually increased,and significant difference was found between every two groups( all P < 0. 05). The expression of LC3 was negatively correlated with Raptor expression in the LGIN group,HGIN group and gastric cancer group( r =-0. 435,-0. 168,and-0. 467,respectively; all P < 0. 05). The expression of Raptor and Rictor were negatively correlated in the LGIN group,HGIN group,and gastric cancer group( r =-0. 260,-0. 312,-0. 223,all P < 0. 05). The expression of LC3,Raptor and Rictor in the early gastric cancer tissues were correlated with the degree of tumor differentiation and depth of invasion( both P < 0. 05). Conclusions Autophagy can promote the occurrence of gastric cancer by promoting the expression of LC3,Raptor,and Rictor. LC3,Raptor,and Rictor play a synergistic role in promoting tumorigenesis.
Objective To investigate the role and mechanism of autophagy in the gastric carcinogenesis.Methods We selected 30 cases of tissues from the normal gastric mucosa,chronic atrophic gastritis,low grade intraepithelial neoplasia( LGIN),and high grade intraepithelial neoplasia( HGIN),and 40 cases of early gastric cancer tissues,which were successively taken as the normal group,gastritis group,LGIN group,HGIN group,and gastric cancer group.The expression of LC3,Raptor,and Rictor of autophagy-related genes was detected by immunohistochemistry. The correlation of LC3,Raptor,and Rictor expression,and the relationship between the expression of LC3,Raptor,and Rictor in early gastric cancer and the clinicopathological parameters were analyzed. Results The expression of LC3 in the normal group,gastritis group,LGIN group,HGIN group,and gastric cancer group gradually increased. There was no significant difference between the LGIN group and the gastritis group,but there was a statistically significant difference among the other groups( all P < 0. 05). The Rictor expression in the gastric cancer group,HGIN group and LGIN group was higher than that in the gastritis group and normal group( P < 0. 05). The Raptor expression in the gastric cancer group was lower than that in the HGIN group and LGIN group( P < 0. 05). The expression of Rictor in the normal group,gastritis group,LGIN group,HGIN group,and the gastric cancer group gradually increased,and significant difference was found between every two groups( all P < 0. 05). The expression of LC3 was negatively correlated with Raptor expression in the LGIN group,HGIN group and gastric cancer group( r =-0. 435,-0. 168,and-0. 467,respectively; all P < 0. 05). The expression of Raptor and Rictor were negatively correlated in the LGIN group,HGIN group,and gastric cancer group( r =-0. 260,-0. 312,-0. 223,all P < 0. 05). The expression of LC3,Raptor and Rictor in the early gastric cancer tissues were correlated with the degree of tumor differentiation and depth of invasion( both P < 0. 05). Conclusions Autophagy can promote the occurrence of gastric cancer by promoting the expression of LC3,Raptor,and Rictor. LC3,Raptor,and Rictor play a synergistic role in promoting tumorigenesis.
引文
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[29]Dresen A,Finkbeiner S,Dottermusch M,et al.Caenorhabditis elegans OSM-11 signaling regulates SKN-1/Nrf during embryonic development and adult longevity and stress response[J].Dev Biol,2015,400(1):118-131.
[30]Tang L,Choe KP.Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans;pleiotrophy,aging,glutathione,and interactions with other longevity pathways[J].Mech Ageing Dev,2015(149):88-98.
[2]Gurzu S,Orlowska J,Sugimura H,et al.Immunohistochemical features and staging of early gastric cancer[J].Arch Med Sci,2017,13(6):1373-1382.
[3]Levy JMM,Towers CG.Targeting autophagy in cancer[J].Nat Rev Cancer,2017,17(9):528-542.
[4]Panda PK,Mukhopadhyay S,Das DN,et al.Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics[J].Semin Cell Dev Biol,2015,3(39):43-55.
[5]中华医学会消化内镜学分会,中国抗癌协会肿瘤内镜专业委员会.中国早期胃癌筛查及内镜诊治共识意见(2014,长沙)[J].中华消化杂志,2014,34(7):433-448.
[6]Schlemper RJ,Riddell RH,Kato Y,et al.The Vienna classification of gastrointestinal epithelial neoplasia[J].Gut,2000,47(2):251-255.
[7]Chen HY,White E.Role of autophagy in cancer prevention[J].Cancer Prev Res(Phila),2011,4(7):973-983.
[8]White E,Di Paola RS.The Double-Edged sword of autophagy modulation in cancer[J].Clin Cancer Res,2009,15(17):5308-5316.
[9]Chen N,Karantza V.Autophagy as a therapeutic target in cancer[J].Cancer Biol Ther,2011,11(2):157-168.
[10]White E,Mehnert JM.Autophagy,metabolism,and cancer[J].Clin Cancer Res,2015,21(22):5037-5046.
[11]Wu S,Sun C,Li Y,et al.Autophagy-related genes Raptor,Rictor,and Beclin1 expression and relationship with multidrug resistance in colorectal carcinoma[J].Human Pathology,2015,46(11):1752-1759.
[12]Rosenfeldt MT,Ryan KM.The multiple roles of autophagy in cancer[J].Carcinogenesis,2011,32(7):955-963.
[13]Shchors K,Massaras A,Hanahan D.Dual targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal autophagy and therapeutic benefit[J].Cancer Cell,2015,12;28(4):456-471.
[14]胡金龙,何双,孙晨博,等.自噬相关基因Beclin1、LC3与大肠癌多药耐药性的相关性[J].临床与实验病理学,2014,30(2):135-139.
[15]Correa P.Human gastric carcinogenesis:a multistep and multifactorial process--Fist American Cancer Society Award Lecture on Cancer Epidemiology and Prevention[J].Cancer Res,1992,52(24):6735-6740.
[16]Qian HR,Yang Y.Functional role of autophagy in gastric cancer[J].Oncotarget,2016,7(14):17641-17651.
[17]Masuda GO,Yashiro M,Kitayama K,et al.Clinicopathological correlations of autophagy related proteins LC3,beclin1 and p62 in gastric cancer[J].Anticancer Res,2016,36(1):129-136.
[18]Liao W,Sun L,Wang C,et al.LC3A-positive"stone-like"structures predict an adverse prognosis of gastric cancer[J].Anat Rec(Hoboken),2014,297(4):653-662.
[19]Levine B.Cell biology:autophagy and cancer[J].Nature,2007,446(7137):745-747.
[20]Wang KF,Yang H,Jiang WQ,et al.Puquitinib mesylate(XC-302)induces autophagy via inhibiting the PI3K/AKT/m TOR signaling pathway in nasopharyngeal cancer cells[J].Int J Mol Med,2015,36(6):1556-1562.
[21]Zhao J,Goldberg AL.Coordinate regulation of autophagy and the ubiquitin proteasome system by m TOR[J].Autophagy,2016,12(10):1967-1970.
[22]Switon K,Kotulska K,Janusz-Kaminska A,et al.Molecular neurobiology of m TOR[J].Neuroscience,2017,2(341):112-153.
[23]Yang G,Murashige DS,Humphrey SJ.A positive feedback loop between Akt and m TORC2 via SIN1 Phosphorylation[J].Cell Rep,2015,12(6):937-943.
[24]Byeon SJ,Han N,Choi J,et al.Prognostic implication of TSC1and m TOR expression in gastric carcinoma[J].J Surg Oncol,2014,109(8):812-817.
[25]Nukazuka A,Tamaki S,Matsumoto K,et al.A shift of the TOR adaptor from Rictor towards Raptor by semaphorin in C.elegans[J].Nat Commun,2011,9(27):484.
[26]Wang X,Yue P,Kim YA,et al.Enhancing mammalian target of rapamycin(m TOR)-targeted cancer therapy by preventing m TOR/raptor inhibition-initiated,m TOR/Rictor-independent Akt activation[J].Cancer Res,2008,68(18):7409-7418.
[27]Webster CM,Wu L,Douglas D,et al.A non-canonical role for the C.elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2[J].Development,2013,140(17):3601-3612.
[28]Ruf V,Holzem C,Peyman T,et al.TORC2 signaling antagonizes SKN-1 to induce C.elegans mesendodermal embryonic development[J].Dev Biol,2013,384(2):214-227.
[29]Dresen A,Finkbeiner S,Dottermusch M,et al.Caenorhabditis elegans OSM-11 signaling regulates SKN-1/Nrf during embryonic development and adult longevity and stress response[J].Dev Biol,2015,400(1):118-131.
[30]Tang L,Choe KP.Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans;pleiotrophy,aging,glutathione,and interactions with other longevity pathways[J].Mech Ageing Dev,2015(149):88-98.