【作者】 段琼红；

【导师】 卢祖洵；

【作者基本信息】 华中科技大学 ， 流行病与卫生统计学， 2005， 博士

【摘要】 研究背景大肠癌(包括结、直肠癌)是一种常见的严重威胁人类生命健康的恶性肿瘤。在发达国家，大肠癌是一个严重的公共卫生问题。在英国和美国，大肠癌是女性除乳腺癌以外的第2大常见肿瘤，是男性除了肺癌、前列腺癌以外的第3大常见肿瘤。在北美和西欧，男、女性大肠癌的发病率分别高达40／10万及25～30／10万。在亚洲，包括我国，其发病率相对较低，但有逐年升高的趋势。从20世纪70年代开始，我国的5个大城市(北京、天津、上海、武汉、哈尔滨)和6个农村地区(河北省磁县、河南省林州县、江苏省启东市、浙江省嘉善县、福建省长乐县、广西自治区扶绥县)相继建立了肿瘤登记系统，收集包括大肠癌在内的恶性肿瘤发病和死亡的资料。据中国12市县1993年～1997年肿瘤发病和死亡登记资料统计分析，大肠癌在城市男性恶性肿瘤的发病、死亡中占第4位，女性恶性肿瘤的发病中占第3位、死亡中占第4位，在农村男性和女性中占第5位。在上述5个大城市中，上海市和北京市大肠癌发病率较高，上海市女性大肠癌的发病率和死亡率分别为32.1／10万和17.9／10万，列第1位，北京市女性大肠癌发病率和死亡率列第2位，其他3个大城市均居第3～5位。在上述6个农村地区中，嘉善县女性大肠癌发病率为22.8／10万，位居发病谱的第1位，其次是江苏省启东市和河南省林州县，而广西扶绥县女性大肠癌发病率最低，为1.2／10万。中国男性大肠癌的发病率和死亡率最高的是浙江省嘉善县，分别为25.6／10万和20.6／10万。1990～1992年中国大城市大肠癌死亡率较1973～1975年上升了31.95％，农村上升了8.51％。在上海，大肠癌的发病率以每年4.2％左右的速度上升。因此，预计我国大肠癌的发病率和死亡率还将继续上升，成为最重要的恶性肿瘤之一。与其他肿瘤一样，国内外学者在大肠癌的基础理论和临床研究方面作了大量工作，并取得许多突破性进展，但值得注意的是，大肠癌病因学的研究仍处于不断进展之中，尚无明确结论，发病机制尚需要进一步阐明。本研究通过对武汉市大肠癌历年死亡资料的分析，预测在未来一段时期大肠癌的死亡趋势；并对武汉市大肠癌新发病人进行调查，探讨大肠癌的发病危险因素；最后，用Meta分析和免疫组织化学等方法对大肠癌的发病机制进行了探索，为完善大肠癌的防治策略和措施开辟新的思路。研究目的1．分析、预测武汉市大肠癌死亡趋势，给有关部门的决策提供新的重要手段。并探讨“等维递补灰数动态预测”方法的可信性，以期为恶性肿瘤发病和死亡趋势的预测提供可靠的方法；2．探讨大肠癌发病的危险因素，有助于确定高危人群，进行病因预防，为有效预防和控制大肠癌提供依据；3．通过Meta分析的方法，获得关于血清IGF-1、IGFBP-3、IGF-2水平和大肠癌关系的可靠证据，初步验证关于大肠癌发病机制的新假说—环境因素通过体内IGF系统促进大肠癌的发生；4．探寻IGF-2、survivin、c-myc三者表达的相关性，明确IGF-2基因表达在大肠癌发生、发展过程中的作用；5．探寻Survivin、bcl-2二者表达的相关性，明确Survivin基因表达在大肠癌发生、发展过程中的作用。材料和方法：1．材料1．1武汉市大肠癌死亡趋势预测：通过武汉市疾病控制机构居民死亡报告登记收集武汉市居民大肠癌的死亡资料。人口资料以1990年全国第四次人口普查资料中的武汉市人口资料为基础，并根据武汉市市区人口变动资料，推算武汉市城区1994～2002年各年度总人口数。1．2武汉市大肠癌危险因素的病例对照研究：武汉市2003～2004年新发大肠癌病例164例和328例对照。1．3血清IGF-1、IGFBP-3、IGF-2与大肠癌关系的Meta分析：利用MEDLINE计算机检索、文献追溯等途径收集国内外1970-2004年期间公开发表的关于血清IGF-1、IGFBP-3、IGF-2与大肠癌关系的研究文献。1．4大肠癌中IGF-2基因的表达及相关性研究：部分患者为1．2中的研究对象中选取，部分为湖北省肿瘤医院、同济医院2005年经病理确诊的患者，共44例。1．5大肠癌中Survivin基因的表达及相关性研究：对象的选择同1．42．方法2．1武汉市大肠癌死亡趋势预测研究方法运用中长期灰色预测方法，即用GM(1，1)建立原始模型，用“等维递补灰数动态预测”进行动态预测。2．2武汉市新发大肠癌危险因素的病例对照研究方法通过病例对照的方法，对164例新发大肠癌病例和328例对照的一般情况和相关危险因素进行调查，首先进行单因素Logistic回归分析，对有显著意义的因素计算其OR值及其95％可信区间(CI)，然后在单因素分析基础上，进行多因素Logistic回归分析。2．3血清IGF-1、IGFBP-3、IGF-2与大肠癌关系的研究方法确定文献资料选入标准，收集并选择文献，阅读文献，按Meta分析的要求整理数据，对不同数据类型，全部转化为OR值及其95％CI形式。采用比值比Q检验法，对研究文献进行一致性检验，若各研究之间的OR齐性，选用M-H法，反之选用随机模型D-L法进行合并。2．4大肠癌中IGF-2基因的表达及相关性研究免疫组化采用SP法。IGF-2、C-myc和survivin分别按1：150、1：100、1：100稀释。检测前，均采用微波抗原修复。2．5大肠癌中Survivin基因的表达及相关性研究免疫组化采用SP法。Bcl-2和survivin均按1：100稀释。检测前，均采用微波抗原修复。研究结果1．武汉市大肠癌死亡趋势预测研究结果2003～2011年武汉市男性大肠癌死亡率预测值分别为(单位：1／10万)：10.156、10.872、11.450、11.998、12.692、13.341、14.031、14.737、15.568；女性为：8.969、9.275、9.454、9.867、9.999、10.290、10.584、10.961、11.223；总人群为：9.576、10.089、10.468、10.943、11.354、11.816、12.298、12.826、13.360。2．武汉市新发大肠癌危险因素的病例对照研究结果慢性阑尾炎病史、一级亲属患肿瘤、情绪调节能力弱、被动吸烟、十年前腌晒盐浸食品食用频率是大肠癌的危险因素，其OR值分别为7.411、3.059、1.782、1.325、1.221；平时饮食喜凉、平时饮食喜软、平时口味清淡是大肠癌的保护因素，其OR值为0.465、0.606、0.615。3．血清IGF-1、IGFBP-3、IGF-2与大肠癌关系的研究结果对于IGF-1，合并OR=1.59(95％CI：1.18-2.16)，按IGFBP-3实验方法不同分层，ELISA法合并OR=1.92，IRMA法合并OR=1.31；对于IGFBP-3，合并OR=0.76(95％CI：0.43-1.33)，按实验方法不同分层，ELISA法合并OR=0.46，IRMA法合并OR=1.34；对于IGF-2，合并OR=2.16(95％CI：1.20-2.89)。4．大肠癌中IGF-2基因的表达及相关性研究1) IGF-2在大肠癌组织中的表达阳性率为27.3％，在切缘组织中的表达阳性率为5.0％，肠癌组织与切缘组织的表达阳性率之比有极显著性差异，P=0.001。IGF-2阳性率与Dukes分期、淋巴转移有关，与组织学分类无关；2) Survivin、c-myc表达阳性与IGF-2表达无明显相关(P＞0.05)。5．大肠癌中Survivin基因的表达及相关性研究1) survivin在大肠癌组织中的表达阳性率为63.6％，在切缘组织中的表达阳性率为0％，肠癌组织与切缘组织的表达阳性率相比有极显著性差异，P＜0.01。survivin表达与患者年龄、肿瘤分化程度、肿瘤大小、部位、Dukes分期、淋巴转移无明显相关性，与性别显著相关；2) Bcl-2表达阳性与survivin表达阳性无明显相关；3) Survivin阳性表达组Ki—67标记指数显著高于阴性组。研究结论1．在今后几年内，武汉市居民大肠癌的死亡率尤其是男性死亡率呈显著上升趋势。在今后几年内，武汉市居民大肠癌的死亡率呈现总体上升的趋势，这一点和其他城市的研究结论相一致。从1994～2000年资料建立的模型外推结果可以看出，2001年的男性死亡率实际值非常接近预测区间的上限，2002年的男性死亡率实际值超过了预测区间的上限，说明现实中有使得男性大肠癌的死亡趋势恶化的环境因子的存在。提示现阶段我们应特别重视男性大肠癌的防治工作。2．为大肠癌的预测提供了新的重要方法——等维递补灰数动态预测法随着预防医学和计算机科学的发展，许多预测方法如趋势外推预测法、Box—Jenkins模型法、组合模型预测法、灰色系统、GM(1，1)模型等逐渐被用于疾病预测。但是以上模型难以满足中长期疾病流行趋势预测的需要，为了进行中长期预测，本研究采用等维递补灰数动态预测方法，以缩小灰平面，在充分利用已知信息的同时，不断补充新的信息，提高灰平面的白色度，从而提高预测精度。本研究发现，此方法建立的模型回代误差较小，外推预测精度较高，完全可以运用到实际工作中去。3．武汉市大肠癌的危险因素在不断变化中，大肠癌的预防工作重点应该因时间而异。武汉市新发病人的危险因素与1999年病人不尽相同。这说明武汉市大肠癌的危险因素在不断变化中，因此大肠癌的预防工作重点应该因时间而异。大肠癌的危险因素包括家族史、既往病史和某些膳食因素和生活方式因素，应从改变饮食习惯、去除不良嗜好、加强情绪调节能力、以及加强高危人群的防治等方面进行武汉市人群大肠癌的预防控制。4．血清IGF-1、IGF-2水平和大肠癌发生相关血清IGF-1高水平、IGF-2高水平为大肠癌的独立危险因子，IGFBP-3与大肠癌的关联不具有统计学意义。本研究发现IGFBP-3与大肠癌关系的各研究之间的异质性是由实验方法不同而引起的，但该结论尚需大样本并同时进行2种方法的测量研究来证实。5．IGF-2可成为预后判断的指标，IGF-2的过表达促进了结肠直肠癌的发生，发展，浸润和转移。本研究显示，IGF-2阳性率与Dukes分期、淋巴转移有关，和其他因素无关，提示IGF-2与大肠癌预后有关，可成为预后判断的指标。6．Survivin基因通过调控细胞增生，参与大肠癌的发生和发展，其蛋白过表达是大肠癌发生中的独立事件。本研究显示，Survivin表达与大肠癌患者性别有关；Survivin基因通过调控细胞增生，参与大肠癌的发生和发展，其蛋白过表达是大肠癌发生中的一种独立事件。对大肠癌的预防和控制工作的建议1．应在现在以及将来一定时期内，加强大肠癌的预防和控制工作；2．政府重视，各部门协调，全社会积极参与大肠癌的防治工作；3．加强恶性肿瘤监测；4．开展以社区为基础的健康教育，倡导健康的生活方式；5．实施大肠癌高危人群策略；6．加强大肠癌发病机制的基础研究。本研究的创新点1．首次运用等维递补灰数动态预测法对大肠癌的死亡率进行预测目前，多采用趋势外推预测法、Box-Jenkins模型法、组合模型预测法等进行肿瘤发病和死亡的预测，尚未见到用灰色理论中的“等维递补灰数动态预测法”进行肿瘤发病和死亡预测的报道。并在预测中引入环境干涉因子，考虑了外环境变化对疾病死亡趋势的影响。环境干涉因子的引入使得死亡率的预测值成为一个区间，而不是一个单一的点值。2．对武汉市大肠癌危险因素进行了较全面的探讨本研究从环境因素和遗传因素两方面对武汉市大肠癌发病危险因素进行了研究，研究变量涵盖内容较广泛，包括个人一般情况、家庭经济文化水平、居住环境条件、饮食习惯、烟酒茶嗜好、体力活动、心理社会因素、体型指数、个人疾病史及家族肿瘤史、女性月经生育史等。3．首次对胰导素样生长因子系统与大肠癌的关系进行了系统综述：环境因素通过体内的胰导素样生长因子(Insulin-like growth factor，IGF)系统而作用于大肠癌的发生是近期的关于大肠癌的新假说之一。本研究利用Meta分析的方法，进行综合评价，揭示了血清IGF-1、IGFBP-3、IGF-2与大肠癌关系。4．首次研究了IGF-2和Survivin基因表达的关系Survivin基因是凋亡抑制家族中的新成员，而IGF-2是近期发现的大肠癌危险因子，关于它们单独和大肠癌关系的研究已经有所报道，但对于两者在大肠癌中联合表达的研究未见报道。更多还原

【Abstract】 Study BackgroundColorectal cancer (including colonic and rectal cancer) is one of the most common cancers that threatening the public health heavily. In the developed world, CRC represents a major public health problem. In the UK and the USA, CRC is the second most common cancer after breast cancer for women, and after prostate or lung cancer for men. The incidence in North America, Western Europe approximates or exceeds 40 cases per 100000 of the population in males and 25-30 cases per 100000 in females. In Asia, so as in China, the incidence is relatively low, but it shows an increase trend.From 20 century 70th, five cities (Beijing,Tianjing,Shanghai,Wuhan, Ha erbing) and six rural areas (Ci county in Hebei Province, Linzhou county in Henan Province, Jianshan county in Zhejiang Province, Changle county in Fujian Province, Fusui county in Guangxi Province) in China have established tumor register system gradually to collect the information about incidence and mortality of malignant tumor including colorectal neoplasm. From 1993 to 1997, the incidence rate and mortality rate of colorectal cancer ranked 3 to 5 among all of the cancers in China. In the five cities, the incidence rate of colorectal cancer is relatively high in Shanghai and Beijing. In Shanghai, the incidence rate and mortality rate is 32.1 cases per 100000 and 17.9 cases per 100000 for female, ranking first; The mortality rate ranked second for female in Beijing and ranked 3th to 5th in other three cities. In rural areas, the incidence rate of colorectal cancer is highest in Jianshan county, where is 22.8 casesper 100000 for female, ranking first in incidence spectrum. Qidong County in Jiangsu Province and Lizhou County in Henan Province is the lower, while Fusui county in Guangxi Province is the lowest, ranked tenth in incidence spectrum. The highest incidence and mortality rate for male is in Jiashan county, Zhejiang Province, where is 25.6 cases per 100000 and 20.6 cases per 100000 respectively. From 1990 to 1992, the mortality rate of colorectal cancer increased 31.95 percent in large city, and 8.51 percent in rural area. In Shanghai, the incidence rate of colorectal cancer increased at a speed by 4.2 percent every year. Therefore, it is expected that the incidence and mortality rate of colorectal cancer will increase in the future. Then, colorectal cancer will become one of the most important malignant tumors.As well as other malignant tumors, great efforts have been conducted by researchers in the field of basic theory and clinical study of colorectal cancer, and many achievements have been gained. But the study of etiology of colorectal cancer is in progress, and has not certain conclusion. The pathogenesis of colorectal cancer need to be explored more.In this study, the data about mortality rate of colorectal cancer in Wuhan city will be analyzed to predict the prevalence trend (mortality rate) of colorectal cancer in Wuhan; The recent risk factors of colorectal cancer in Wuhan will be investigated; At last, pathogenesis of colorectal cancer will be explored by Meta analysis and immunohisochemistry, to provide basis for the prevention of colorectal cancer.Objectives of Study1. To predict the prevalence trend (mortality rate) of colorectal cancer in Wuhan, and explore the reliability of the Grey Model;2. To investigate the recent risk factors of colorectal cancer in Wuhan, and provide correspondingly preventive measures and screening methods for colorectal cancer;3. To evaluate the relationship between circulating levels of IGF-1、 IGFBP-3 and IGF-2 and colorectal cancer by Mata analysis, to prove the new hypothesis of colorectal cancer—environmental factors influence the risk of colorectal cancer by IGF system;4. To study the relationship between IGF-2 expression and the biological behavior， the expression of survivin, c-myc in colorectal cancer cases;5. To study the relationship between survivin expression and the biological behavior， the expression of bcl-2 and ki index in colorectal cancer cases.Subject (Material) and Method 1. Subject1.1 Research on the Prediction of the Prevalence of Colorectal Cancer:To collect the mortality data through death register system in Wuhan Disease Control Center. The total number of Wuhan population in 1994-2002 was calculated basing on the data of Wuhan population from the forth China population census and the variation data of Wuhan population.1.2 Research on recent Risk Factors of Colorectal Cancer in Wuhan, China: Sample size was estimated according to α =0.05 and power of test (1-β)=0.9 before we conducted a unpaired case-control study for this program. From 1st March 2003 to 30th September 2004, 164 patients diagnosed by pathology were selected from three comprehensive hospitals and one tumor-specialized hospital in Wuhan including 100 male and 64 female patients.1.3 Meta-analysis on serum IGF-1 、 IGFBP-3、 IGF-2 and colorectal cancer: eight epidemiological studies on insulin-like growth factors and risk of colorectal cancer were selected by Internet.1.4 Expression of IGF-2 gene in colorectal cancer and its significance:Samples were selected from the subject of 1.2 and cases in Hubei tumour hospital in 20051.5 Expression of survivin gene in colorectal cancer and its significance: The selection of sample is the same as 1.42.Methods2.1 Research on the Prediction of the Prevalence of Colorectal Cancer:the prediction model was established based on the Grey Model, predicting the resultdynamically using "Same Dimension-Progressively Increased Grey DynamicPrediction", modifying the prediction results by considering the "EnvironmentInterference Factors".2.2 Research on recent Risk Factors of Colorectal Cancer in Wuhan, China:With case-control study, after investigating candidate colorectal cancer risk factorinformation and general information of 164 cases and 328 control people,single-factor logistic regression analysis was firstly used to calculate OR value and95% C.I. of significant factors. Then multi-factor logistic regression analysis was usedon the basis of single-factor analysis.23 Meta-analysis on serum IGF-1, IGFBP-3, IGF-2 and colorectal cancer:We performed a meta-analysis of 8 epidemiological studies on insulin-like growthfactors and risk of colorectal cancer2.4 Expression of IGF-2 gene in colorectal cancer and its significance:The expression of IGF-2, survivin, c-myc and ki index was detected in 44 cases of the primary colorectal cancer, 20 cases of the normal tissue by using immunohistochemical SP.2.5 Expression of survivin gene in colorectal cancer and its significance:The expression of survivin, bcl-2 and ki index was detected in 44 cases of the primary colorectal cancer, 20 cases of the normal tissue by using immunohistochemical SP.Results1. Research on the Prediction of the Prevalence of Colorectal Cancer: The mid-time and long-term predictions about mortality rate of colorectal cancer were made based on the GM(1,1) model. The predicting value of mortality rate in 2003～ 2011 for males is(unit:l per 100000): 10.156、 10.872、 11.450、 11.998、 12.692、 13.341、 14.031、 14.737、 15.568; For females is: 8.969、 9.275、 9.454、 9.867、 9.999, 10.290, 10.584, 10.961, 11.223; For whole population is: 9.576, 10.089, 10.468、 10.943、 11.354、 11.816、 12.298、 12.826, 13.360. The measurements about how to prevent colorectal cancer were summarized according to the results of thisresearch.2. Research on recent Risk Factors of Colorectal Cancer in Wuhan, China:That the history of chronic appendicitis, first degree relatives who suffered fromcancer, the poor ability of adjusting the mood, passive smoking, and the frequency ofsalted foods ten years ago were closely associated with colorectal cancer. Thecorresponding adjusted Odds Ratio (ORs) were 7.411(95%CI: 2.413-22.760),3.059(95%CI: 1.718-5.450), 1.782(95%CI: 1.328-2.389), 1.325(95%CI: 1.147-1.530)and 1.221(95%CI: 1.114-1.340) respectively. There was a protective effect providedby the habit of eating cool foods, eating soft foods, low-salted foods for colorectalcancer, the corresponding adjusted ORs were 0.465(95%CI: 0.333-0.647),0.606(95%CI: 0.470-0.781) and 0.615(95%CI: 0.480-0.790) respectively.3.A meta-analysis on serum IGF-1、 IGFBP-3、 IGF-2 and colorectal cancer:The pooled odds ratio(OR) of IGF-1 and IGFBP-3 were 1.59 and 0.76 respectively.According to the different measurements(ELISA and IRMA) , the pooled OR was1.92 and 1.31 for IGF-1, 0.46 and 1.34 for IGFBP-3 respectively. The pooled OR ofIGF-2 was 2.16.4.Expression of IGF-2 gene in colorectal cancer and its significance:1) The positive rates of survivin expression were 27.3% in cancer tissue and 5.0% inmarge tissue respectively. The difference between them was significant. Significantrelationships were found between IGF-2 expressions and Duke’s stage, lymphmetastasis of colorectal cancer (P<0.05).2)The c-myc, survivin expression was not associated with the IGF-2 expression(P>0.05).5. Expression of survivin gene in colorectal cancer and its significance:1) The positive rates of survivin expression were 63.6% in cancer tissue and 0% in tumor marge tissue respectively. The difference between them was significant. Significant relationships were found between survivin expressions and sex of colorectal cancer cases(P<0.05).2) The bcl-2 expression was not associated with the survivin expression (P>0.05).3) The mean Ki in survivin positive tumors was significant higher than that insurvivin negative tumors(P<0.01).Conclusions1. In the recent future, the mortality rate of colorectal cancer in Wuhan, especially formale, showed a significant increase trend.This situation is similar with other cities. From the results of model based on1994-2000 data, we can see that the real male mortality rate in 2001 is close to theupper limit of prediction interval, and is beyond the upper limit of prediction intervalin 2002. It shows that there are environmental factors leading to increase the malemortality rate.2.This research provided new and important means for prediction of colorectal cancer.The short-term prediction results have been confirmed and the long-term predictionneed to be further studied.3. The recent risk factors of colorectal cancer is different from old studiesThe above findings indicate that the risk of colorectal cancer is significantly associated with the history of chronic appendicitis, family history of cancers, psychological factors, and dietary factors.4. IGF-1 and IGF-2 are associated with colorectal cancerHigh serum levels of IGF-1 and IGF-2 were the independent risk factors of colorectal cancer, and the OR of IGFBP-3 was not statistically significant. The heterogeneity between studies on IGFBP-3 and colorectal cancer was due to the different measurement, but there is still a need to conduct large size study using 2 different measurements simultaneously to further prove it.5. IGF-2 is a prognostic factor, and it is included in the pathogenesis of colorectal cancer. IGF-2 expression is associated with malignant degree of colorectal cancer, and detection of it has positive effects on prognosis evaluation.6. Survivin is included in the pathogenesis of colorectal cancerSurvivin expression is associated with sex of colorectal cancer cases. Survivin plays certain roles in the oncogenesis and progression of colorectal cancer.Suggestion to the prevention of colorectal cancer1.We should put emphasis on the prevention and control work of colorectal cancer atpresent and in recent future. 2.The government should be involved in the work of colorectal cancer control andprevention.3.Strengthen the surveillance of colorectal cancer4.Undertake the health education in community, advocate the healthy life-style 5.Implement high-risk group strategy 6.Reinforce the study of pathogenesis of colorectal cancerCreative Points of the study1. Firstly use "Same Dimension-Progressively Increased Grey Dynamic Prediction" topredict the prevalence trend of colorectal cancerAt present, the methods which are usually used to predict prevalence and mortalitytrend of malignant tumor are trend extrapolation, Box-Jenkins model, mixed model.The "Same Dimension-Progressively Increased Grey Dynamic Prediction" has notbeen seen in the field of malignant tumor prediction.2.Study the recent risk factors of colorectal cancer in Wuhan thoroughlyThis study investigated the risk factor from both environmental and hereditaryaspects.3. Evaluate the relationship between circulating levels of IGF-1、 IGF-2、 IGFBP-3 andcolorectal cancer by meta-analysis firstlyWe performed a meta-analysis of 8 epidemiological studies on insulin-like growthfactors and risk of colorectal cancer. The results showed that high serum levels ofIGF-1 and IGF-2 were the independent risk factors of colorectal cancer, and the ORof IGFBP-3 was not statistically significant. This is the first meta-analysis study about1GF-1、 IGF-2、 IGFBP-3 and colorectal cancer.4.Study the relationship between IGF-2 and Survivin expression firstlySurvivin is the new member of Inhibition Apoptosis Protein, while IGF-2 is a riskfactor for colorectal cancer recently mentioned. There are some report about thecolorectal cancer and these two genes individually, but the jointed expression of them is lacked.更多还原