本文選題：鋸齒狀息肉 + 傳統(tǒng)腺瘤��； 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的結(jié)直腸癌(colorectal cancer,CRC)為消化系統(tǒng)常見(jiàn)惡性腫瘤,為癌癥致死的常見(jiàn)病因。大腸息肉為消化系統(tǒng)常見(jiàn)病,與CRC的發(fā)生密切相關(guān),其主要包含兩種息肉類(lèi)型,即鋸齒狀息肉(SPs)和傳統(tǒng)腺瘤(CA),其中鋸齒狀息肉又包含三種亞型:增生性息肉、無(wú)蒂平坦型鋸齒狀息肉伴或不伴細(xì)胞異型性及傳統(tǒng)鋸齒狀腺瘤。大多數(shù)CRC由傳統(tǒng)腺瘤經(jīng)傳統(tǒng)的“腺瘤-腺癌途徑”發(fā)展而成,而目前有研究認(rèn)為,大約有1/3的CRC由鋸齒狀息肉經(jīng)“鋸齒狀途徑”演變而來(lái)。既往已有研究探討兩類(lèi)息肉的風(fēng)險(xiǎn)因素及其差異,但性別、年齡等因素對(duì)疾病的影響仍存在爭(zhēng)議。本研究通過(guò)分析對(duì)比鋸齒狀息肉及傳統(tǒng)腺瘤的風(fēng)險(xiǎn)因素,從病因?qū)W角度探討兩類(lèi)病變間差異,為高危人群的篩查提供參考信息,有利于醫(yī)療資源的高效利用,同時(shí),對(duì)兩類(lèi)病變高危人群是否需要進(jìn)行“差異化”管理進(jìn)行探討。近來(lái),越來(lái)越多的研究表明炎癥微環(huán)境在腫瘤發(fā)生、發(fā)展的各個(gè)階段中均發(fā)揮著至關(guān)重要的作用,這其中也包括了 CRC�；罨难装Y細(xì)胞可產(chǎn)生活性氧及活性氮介質(zhì),并能利用細(xì)胞因子使活性氧在周?chē)掀ぜ?xì)胞中聚集�；钚匝跫盎钚缘橘|(zhì)可導(dǎo)致DNA的損傷及基因組的不穩(wěn)定性,增加基因突變率,從而促使腫瘤的發(fā)生。另一方面,腫瘤組織中的炎癥及免疫細(xì)胞可分泌多種炎癥介質(zhì),這些炎癥介質(zhì)與相應(yīng)的受體結(jié)合,導(dǎo)致JAK-STAT、MAPK等信號(hào)通路的持續(xù)激活,促進(jìn)下游Bcl-XL、Bcl-2、MYC、MMP2等靶基因的轉(zhuǎn)錄,作用于細(xì)胞的增殖、生長(zhǎng)過(guò)程,從而促進(jìn)腫瘤細(xì)胞的增殖、浸潤(rùn)及轉(zhuǎn)移。炎癥微環(huán)境可促進(jìn)晚期CRC的發(fā)展,這一觀點(diǎn)目前已得到廣泛認(rèn)可,但其與尚處于癌前階段的大腸息肉之間的關(guān)系尚不明確。既往已有多項(xiàng)研究探討兩類(lèi)病變基因水平發(fā)病機(jī)制的差異。本研究擬進(jìn)一步分析炎癥微環(huán)境與兩類(lèi)病變發(fā)生發(fā)展的關(guān)系,進(jìn)一步探討兩類(lèi)病變發(fā)病機(jī)制的異同,為藥物預(yù)防CRC提供參考信息。方法風(fēng)險(xiǎn)因素分析:收集南方醫(yī)院消化內(nèi)鏡中心2012-2015行全結(jié)腸鏡及息肉病理檢查的病例。按病例入組標(biāo)準(zhǔn)從入選病例中隨機(jī)選取健康對(duì)照103例,鋸齒狀息肉100例(增生性息肉66例,無(wú)蒂平坦型鋸齒狀息肉伴或不伴細(xì)胞異型性21例,傳統(tǒng)鋸齒狀腺瘤13例),傳統(tǒng)腺瘤115例(輕度不典型增生71例,中度不典型增生34例,重度不典型增生10例)。收集各病例性別、年齡、身高、體重等臨床數(shù)據(jù)用于分析。發(fā)病機(jī)制研究:選取南方醫(yī)院消化內(nèi)鏡中心2012年-2016年行結(jié)腸鏡檢查及息肉病理診斷的病例,從中選取鋸齒狀息肉53例(增生性息肉12例,無(wú)蒂平坦型鋸齒狀息肉不伴細(xì)胞異型性17例、伴細(xì)胞異型性5例,傳統(tǒng)鋸齒狀腺瘤低級(jí)別瘤變11例、高級(jí)別瘤變8例),傳統(tǒng)腺瘤44例(低級(jí)別瘤變26例,高級(jí)別瘤變18例)。選取南方醫(yī)院消化內(nèi)鏡中心2016年11月至12月期間行結(jié)腸鏡檢查且未見(jiàn)異常者11例作為正常粘膜對(duì)照。運(yùn)用免疫組織化學(xué)染色法檢測(cè)石蠟包埋標(biāo)本中COX-2、IL-6、p-STAT3、Ki-67的表達(dá)。結(jié)果風(fēng)險(xiǎn)因素分析:SPs平均發(fā)病年齡48.87歲(95%CI 47.22-50.52),較CA更早(P=0.038)。以青年組為參照,中年組發(fā)生SPs風(fēng)險(xiǎn)增加2.31倍(95%CI 1.46-3.65)、CA風(fēng)險(xiǎn)增加4.10倍(95%CI 2.50-6.72);老年組發(fā)生SPs風(fēng)險(xiǎn)增加 2.77 倍(95%CI 1.52-5.04)、CA 風(fēng)險(xiǎn)增加 6.00 倍(95%CI 3.26-11.05)。其中,年齡與CA的發(fā)生較SPs關(guān)系更為密切(老年組:OR=2.14,95%CI 1.21-3.78,P=0.009)。男性較女性SPs發(fā)病風(fēng)險(xiǎn)增加2.75倍(95%CI 1.50-5.07)、CA增加2.19倍(95%CI 1.22-3.95)。BMI每增加1個(gè)單位,SPs發(fā)病風(fēng)險(xiǎn)增加1.18倍(95%CI 1.06-1.30)、CA 增加 1.20 倍(95%CI 1.09-1.32)。發(fā)病機(jī)制研究:COX-2、IL-6、p-STAT3、Ki-67在傳統(tǒng)腺瘤中的表達(dá)均強(qiáng)于正常粘膜(COX-2:P=0.004;IL-6:P=0.004;p-STAT3:P=0.001;Ki-67:P=0.018)。而在鋸齒狀息肉中,僅p-STAT3的表達(dá)強(qiáng)于正常粘膜,余均無(wú)顯著性差異(COX-2:P=0.881;IL-6:P=0.484;p-STAT3:P=0.001;Ki-67:P=0.287)。傳統(tǒng)腺瘤與鋸齒狀息肉進(jìn)行比較,COX-2、IL-6、Ki-67在傳統(tǒng)腺瘤中的表達(dá)均高于鋸齒狀息肉(COX-2:P=0.003;IL-6:P=0.0.044;Ki-67:P=0.029),而p-STAT3在兩者中的表達(dá)并無(wú)顯著性差異(P=0.991)。COX-2、IL-6、p-STAT3、Ki-67在鋸齒狀息肉不同亞型中的表達(dá)并無(wú)顯著性差異(COX-2:P=0.534;IL-6:P=0.369;p-STAT3:P=0.054;Ki-67:P=0.601)。COX-2、IL-6、p-STAT3、Ki-67在無(wú)蒂平坦型鋸齒狀息肉不同發(fā)展階段中的表達(dá)無(wú)顯著性差異(COX-2:P=0.359;IL-6:P=0.649;p-STAT3:P=0.319;Ki-67:P=1.000);在傳統(tǒng)鋸齒狀腺瘤不同發(fā)展階段中的表達(dá)無(wú)顯著性差異(COX-2:P=0.152;IL-6:P=0.177;p-STAT3:P=0.129;Ki-67:P=0.051);在傳統(tǒng)腺瘤不同發(fā)展階段中的表達(dá)無(wú)顯著性差異(COX-2:P=0.189;IL-6:P=0.283;p-STAT3:P=0.512;Ki-67:P=0.896)。結(jié)論兩類(lèi)息肉風(fēng)險(xiǎn)因素均為年齡、男性、BMI,僅年齡與傳統(tǒng)腺瘤的發(fā)生關(guān)系更為密切,對(duì)兩類(lèi)息肉高危人群的篩查可考慮使用同一方案。SPs平均發(fā)病年齡早于50歲,而其具有快速進(jìn)展的潛能,建議50歲前即開(kāi)始進(jìn)行CRC篩查。炎癥微環(huán)境可促進(jìn)腸上皮細(xì)胞的增殖;炎癥微環(huán)境參與了傳統(tǒng)腺瘤及鋸齒狀息肉的發(fā)生發(fā)展,抗炎藥物或可抑制大腸息肉的發(fā)生發(fā)展;NSAIDs類(lèi)抗炎藥物或僅對(duì)傳統(tǒng)腺瘤的發(fā)生發(fā)展具有抑制作用,而對(duì)鋸齒狀息肉不具有抑制作用。對(duì)于鋸齒狀息肉,p-STAT3或?yàn)楦档每紤]的藥物作用靶點(diǎn)。
[Abstract]:Colorectal cancer (CRC) is a common malignant tumor of the digestive system. It is a common cause of cancer death. Colorectal polyps are common diseases of the digestive system. It is closely related to the occurrence of CRC. It mainly contains two types of polyps, namely, serrated polyps (SPs) and traditional adenomas (CA), of which serrated polyps include three subtypes: hyperplasia Sexual polyps, no pedicle type serrated polyps with or without cell heterotypic and traditional serrated adenomas. Most of the CRC is developed by traditional adenoma adenocarcinoma pathway. Currently, some studies have suggested that about 1/3 CRC evolved from the serrated path of the serrated polyps. Two types of previous studies have been studied. The risk factors and differences of polyps are still disputed, but the influence of sex, age and other factors on the disease is still controversial. By analyzing and comparing the risk factors of serrated polyps and traditional adenomas, this study explores the differences between the two types of lesions from the point of view of the etiology, and provides information for the screening of high-risk groups, which is beneficial to the efficient use of medical resources, and at the same time, The need for "differential" management of two types of high-risk groups is discussed. Recently, more and more studies have shown that the inflammatory microenvironment plays a vital role in the development of the tumor. It also includes that CRC. activated inflammatory cells can produce living oxygen and active nitrogen medium and can be used. Cytokine causes the accumulation of active oxygen in the surrounding epithelial cells. Active oxygen and active nitrogen medium can cause DNA damage and genomic instability, increase gene mutation rate, and promote the occurrence of tumor. On the other hand, inflammation and immune cells in the tumor tissue can secrete a variety of inflammatory mediators, these inflammatory mediators and corresponding receptors. Combined, it leads to the continuous activation of JAK-STAT, MAPK and other signaling pathways, promoting the transcription of target genes, such as Bcl-XL, Bcl-2, MYC, MMP2, and other target genes in the downstream, acting on the proliferation and growth process of the cells, thus promoting the proliferation, infiltration and metastasis of the tumor cells. The inflammatory microenvironment can promote the development of late CRC. This view has been widely recognized, but it is still in place. The relationship between colorectal polyps in the precancerous stage is not clear. There have been a number of previous studies to explore the differences in the pathogenesis of the two types of lesions. This study intends to further analyze the relationship between the inflammatory microenvironment and the development of the two types of lesions, further explore the similarities and differences of the pathogenesis of the two types of lesions, and provide reference information for the prevention of CRC. Method analysis of risk factors: 2012-2015 cases of total colonoscopy and polyp pathological examination were collected from the digestive endoscopy center of the southern hospital. According to the standard of case entry, 103 cases of healthy control, 100 cases of serrated polyps (66 cases of proliferative polyps, 21 cases of non pedicle saw polyps with or without cell heterotyping) were selected. 13 cases of serrated adenoma, 115 cases of traditional adenoma (71 cases of mild atypical hyperplasia, 34 cases of moderate atypical hyperplasia, 10 cases of severe atypical hyperplasia). The clinical data of sex, age, height, weight, etc. were collected for analysis of the pathogenesis of each case. Study on the pathogenesis of the cancer endoscopy center of the southern hospital in 2012 -2016 and polyp pathological examination 53 cases of serrated polyps (12 cases of proliferative polyps, 17 cases without pedicle flat serrated polyps without cell atypia, 5 cases with cellular atypia, 11 cases of low grade adenoma with traditional serrated adenoma, 8 cases of advanced tumor change), 44 cases of traditional adenoma (26 cases of low grade neoplasia, 18 cases of advanced tumor and 18 cases) were selected from the digestive tract of the southern hospital. The expression of COX-2, IL-6, p-STAT3 and Ki-67 in paraffin embedded specimens was detected by immunohistochemical staining in 11 cases who underwent colonoscopy from November 2016 to December. The results of risk factors were 48.87 years (95%CI 47.22-50.52), compared with CA earlier (P=0.038). In the middle age group, the risk of SPs increased by 2.31 times (95%CI 1.46-3.65), and the risk of CA increased by 4.10 times (95%CI 2.50-6.72); the risk of SPs increased by 2.77 times (95%CI 1.52-5.04) in the elderly group, and CA risk increased by 6 times (95%CI 3.26-11.05). 9. The risk of SPs increased by 2.75 times (95%CI 1.50-5.07), and CA increased by 2.19 times (95%CI 1.22-3.95).BMI in 1 units. The risk of SPs increased by 1.18 times (95%CI 1.06-1.30) and CA increased 1.20 times (95%CI). P=0.004; IL-6:P=0.004; p-STAT3:P=0.001; Ki-67:P=0.018). But in the serrated polyps, only p-STAT3 expression is stronger than normal mucous membrane, and there is no significant difference (COX-2:P=0.881; IL-6:P=0.484; p-STAT3:P=0.001; Ki-67:P=0.287). Traditional adenomas are compared with serrated polyps, COX-2, IL-6, and Ki-67 in traditional adenomas are higher than sawmills. The expression of COX-2:P=0.003 (IL-6:P=0.0.044; Ki-67:P=0.029) was not significant (P=0.991).COX-2, IL-6, p-STAT3, and Ki-67 in different subtypes of serrated polyps (COX-2:P=0.534; IL-6:P= 0.369; p-STAT3:P=0.054; There is no significant difference in the expression of flat serrated polyps at different stages of development (COX-2:P=0.359; IL-6:P=0.649; p-STAT3:P=0.319; Ki-67:P=1.000); there is no significant difference in the expression of the traditional serrated adenoma at different stages of development (COX-2:P=0.152; IL-6:P=0.177; p-STAT3:P=0.129; Ki-67:P=0.051); in the different developmental stages of the traditional adenoma There was no significant difference in expression (COX-2:P=0.189; IL-6:P=0.283; p-STAT3:P=0.512; Ki-67:P=0.896). Conclusion the risk factors of two types of polyps were age, male, BMI, and the age was more closely related to the occurrence of traditional adenomas. The screening of two groups of high-risk groups of polyps could consider the same scheme as the average age of.SPs at the age of 50. With the potential of rapid progress, it is suggested that CRC screening begins before 50 years of age. Inflammatory microenvironment can promote the proliferation of intestinal epithelial cells; inflammatory microenvironment participates in the development of traditional adenomas and serrated polyps, the development of anti-inflammatory drugs or the inhibition of colorectal polyps; NSAIDs antiinflammatory drugs or only the development of traditional adenomas Inhibition has no inhibitory effect on serrated polyps. For serrated polyps, p-STAT3 is a more worthy drug target.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.3;R574

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