摘要
胃泌素（Gastrin，GAS）最早于1905年由John在胃窦黏膜提取物中发现，并认为其与胃酸分泌有关，直到1964年才由Gregory和Tracy分离鉴定并阐述其化学结构，确认其为胃肠激素。胃泌素是一种重要的胃肠激素，主要由消化道的G细胞分泌，G细胞是典型的开放型细胞，以胃窦部最多。作为一种营养性胃肠肽，不仅能刺激正常胃肠道黏膜组织的生长，而且还能刺激胰腺癌、胆囊癌、大肠癌及胃癌等肿瘤细胞的生长。近来众多研究认为胃泌素是一种自分泌生长因子，它可以通过自分泌、旁分泌、神经内分泌等方式发挥作用。胃泌素与其受体结合后可通过细胞内信号传导途径调节肿瘤细胞的生长，即肿瘤细胞产生的胃泌素与其自身的受体结合后，发挥其生物学效应。近年来研究已证实部分大肠癌的发生与胃泌素表达异常有关，这一类大肠癌有学者把它们称为激素依赖性肿瘤，其促进大肠癌细胞增殖的机制可能是通过自主性地产生和分泌胃泌素并作用于自身细胞膜上的受体，从而发挥生物学效应，但其作用能被胃泌素受体拮抗剂所抑制，但胃泌素调节大肠癌细胞增殖的分子机制仍不清楚。
近年来，通过应用基因芯片技术对大肠癌相关基因检测，筛选出大量差异表达基因,在显著差异表达的基因中,许多与细胞内外网络信号转导通路的激活与抑制密切相关，直接参与细胞的物质代谢、增殖、分化和凋亡的调节。有关丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)信息转导通路的研究近来倍受关注，MAPK是细胞内一类丝氨酸/苏氨酸蛋白激酶，广泛存在于大多数哺乳动物细胞质和细胞核中，能够将细胞外刺激信号传导至细胞内及细胞核内，并引起细胞生物学反应,调节细胞的增殖、分化、发育和凋亡。丝裂原活化蛋白激酶主要分为细胞外信号调节激酶(extracellular-signal regulated protein kinase， ERK)、 c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）/应激活化蛋白激酶（stress-activated protein kinase，SAPK）、ERK5/BMK1和p38等MAPK亚族，这些亚族组成多条信号转导通路。目前研究已发现哺乳动物类细胞存在三条并行的丝裂原活化蛋白激酶信号通路，分别为为ERK信号通路、p38信号转导通路和JNK/SAPK信号转导通路。其中，JNK/SAPK和p38两条信号转导通路主要与细胞的凋亡和应激有关，而ERK信号通路在MAPK细胞信号转导网络中处于枢纽地位，它主要与细胞的增殖和分化密切相关。众多的研究提示MAPK信号转导通路参与了大肠癌细胞生长的调控。近来研究发现，胃泌素可通过激活p38MAPK信号转导通路诱导大肠癌细胞尿激酶型纤溶酶原激活物(u-PA)表达，进而增强肿瘤细胞的侵袭力和转移过程。可见，丝裂原活化蛋白激酶信号转导通路在胃泌素调节大肠癌生长中起着重要作用，但其机制仍不清楚。
因此我们设想首先运用ELISA法对79例大肠癌手术切除标本检测，筛选出胃泌素表达阳性及阴性的大肠癌组织标本，并对其阳性表达率、组织病理类型、分化程度及临床Duke’s分期进行分析，明确胃泌素对大肠癌生物学特性的影响。其次，分别选择5对胃泌素表达阳性的大肠癌组织及癌旁正常粘膜组织，以及5对胃泌素表达阴性的大肠癌组织及癌旁正常粘膜组织，利用基因芯片技术分别对其差异基因表达谱进行分析，将阳性组与阴性组分析结果进行比较，筛选出表达明显差异的基因，并选择明显表达差异的基因进行real-time PCR验证，同时将明显表达差异基因导入R package中，筛选出与MAPK信号转导通路相关的差异基因。最后，通过大肠癌细胞株HT-29的培养，应用Western blot、RT-PCR等技术分别对各组已筛选出MAPK信号转导通路明显相关的差异基因及其蛋白表达情况进行检测，并分析胃泌素在其受体拮抗剂丙谷胺阻断其前后对其表达变化影响，从分子信号传导水平探索大肠癌组织中胃泌素调节MAPK信号转导通路的分子机制；明确“GAS-MAPK-靶基因”信号转导通路在胃泌素调节大肠癌生长中的详细分子基础，为有效地干预其信号转导通路环节提供新的线索，为基因靶向治疗提供新目标，并为大肠癌的内分泌治疗提供更充分的理论依据。
研究分三个部分：
第一部分：大肠癌组织中胃泌素表达检测及生物学行为分析
目的：探讨大肠癌组织中胃泌素阳性表达率以及胃泌素对组织病理类型、分化程度及临床Duke’s分期等大肠癌生物学特性的影响。方法：运用ELISA法和RT-PCR技术对79例大肠癌手术切除标本检测，筛选出胃泌素表达阳性及阴性的大肠癌组织标本，并对其阳性表达率、组织病理类型、组织分化程度及Duke’s分期进行分析。
结果：79例大肠癌组织中GAS mRNA表达阳性率为46.8％(36/79)，蛋白表达阳性率为40.5％(32/79)；GAS mRNA与其蛋白表达呈正相关（r=0.99, P<0.01）。GAS mRNA及其蛋白在高、中分化组织的阳性表达率明显低于低分化（P<0.05）。GAS mRNA及其蛋白在乳头状腺癌、管状腺癌的阳性表达率明显低于粘液印戒细胞癌及未分化癌（P<0.05）。DukesA,B期的GAS mRNA及其蛋白阳性表达率明显低于C,D期（P<0.05）。
结论：部分大肠癌组织中存在胃泌素的表达，胃泌素的异常表达与组织分化程度、病理类型及临床Duke’s分期密切相关，胃泌素检测能够反应部分大肠癌的生物学特性，可作为临床大肠癌生物学行为的评估指标之一。
第二部分：胃泌素表达阳性与阴性的大肠癌组织中MAPK信号转导通路差异基因筛选
目的：探讨胃泌素表达阳性与阴性的大肠癌组织中MAPK信号转导通路相关差异基因表达。
方法：应用基因芯片技术分别对大肠癌胃泌素表达阳性的癌组织、癌旁正常组织以及大肠癌胃泌素表达阴性的癌组织、癌旁正常组织中MAPK信号通路相关的差异基因表达谱进行分析，并将两组分析结果进行比较，筛选出表达明显差异的基因，并选择明显表达差异的基因进行real-time PCR验证，同时将所有差异表达基因导入Rpackage中，筛选出与MAPK信号转导通路相关的差异基因。
结果：胃泌素表达阳性的癌组织与癌旁正常粘膜组织基因芯片分析结果显示：上调2倍以上的差异基因有3529个，下调2倍以下的差异基因3328个；胃泌素表达阴性的癌组织与癌旁正常粘膜组织基因芯片分析结果显示：上调2倍以上的差异基因有2867个，下调2倍以下的差异基因2549个。将两组分析的差异基因以癌组织的荧光值标记，并进行与胃泌素相关的差异基因分析，结果显示：上调2倍以上的差异基因有567个，下调2倍以下的差异基因342个。并筛选出与MAPK信号转导通路相关的差异基因78。分别选择上调和下调基因各3个进行基因验证，验证结果显示：PCR与芯片分析结果基本一致。
结论：cDNA微阵列法可以用于胃泌素相关的大肠癌的相关基因的筛选，获得的差异基因具有强烈的代表性。大肠癌组织中胃泌素表达阳性与阴性之间存在着差异基因的表达；MAPK信号转导通路参与了胃泌素对大肠癌细胞生长的调控。第三部分：MAPK信号转导通路在胃泌素调节大肠癌细胞增殖与凋亡中
的作用及机制
目的：探讨胃泌素对体外培养的人大肠癌细胞株HT-29增殖、凋亡的影响，以及与MAPK信号转导通路的关系。
方法：通过体外对大肠癌HT-29细胞株的培养，分别运用MTT法观察细胞增生活力改变情况，确立5-肽胃泌素（pentagastrin, PG）和丙谷胺(proglumide, PGL)处理HT-29细胞的最佳浓度；流式细胞仪Annexin V-FITC法检测各组细胞增殖指数(proliferationindex, PI)及凋亡率(apoptosis rate, AR)的变化；RT-PCR检测大肠癌HT-29细胞株胃泌素受体CCK-BR mRNA表达情况以及各组ERK1/2、K-ras、p38、bax、bcl-2mRNA表达水平的变化；Western blot法检测ERK1/2、K-ras、p38、bax、bcl-2蛋白表达及其ERK1/2、K-ras、p38磷酸化水平。
结果：胃泌素浓度在6.25～100.00mg/L范围内能促进大肠癌HT-29细胞的增殖抑制凋亡，且度增加到25.00mg/L时OD值最大，促增生能力最强（P<0.05）；胃泌素受体拮抗剂丙谷胺单独对大肠癌HT-29细胞增殖、凋亡无明显影响，但丙谷胺在一定浓度范围内(8.00～128.00mg/L)能明显拮抗胃泌素促进HT-29细胞的增殖作用,其最佳浓度为32.00mg/L（P<0.05）。胃泌素组细胞增殖指数显著高于对照组和胃泌素+丙谷胺组（P<0.01）；胃泌素组凋亡率显著低于对照组和胃泌素+丙谷胺组（P<0.05）；HT-29细胞中存在明显的CCK-BR mRNA表达；PG组(0.43±0.04,0.45±0.06)与对照组(0.32±0.02,0.31±0.05)及PG+PGL组（0.36±0.01，0.35±0.04）相比，ERK1/2、K-ras磷酸化水平明显升高，而p38磷酸化水平明显降低（P<0.05），ERK1/2、K-ras及p38mRNA及蛋白表达无明显差异；胃泌素组与对照组和胃泌素+丙谷胺组比较bax mRNA及蛋白表达明显降低、Bcl-2mRNA及蛋白表达明显增高（P<0.05）。
结论：胃泌素能够促进大肠癌HT-29细胞增殖、抑制凋亡，但能被其受体拮抗剂丙谷胺抑制。其机制可能是通过激活ERK-MAPK信号通路中Ras→Raf→MEK1/2→ERK1/2途径促进大肠癌HT-29细胞增殖；通过激活p38-MAPK信号通路中p38MAPK→bcl-2/bax途径抑制大肠癌HT-29细胞凋亡。
Gastrin (Gastrin, GAS) was found by John as early as1905in the extracts of gastricantral mucosa and its associated with gastric acid secretion, Until1964it was isolated andidentified by Gregory and Tracy and explains its chemical structure, confirmed asgastrointestinal hormones. Gastrin is a kind of important gastrointestinal hormone and akind of gastrointestinal peptide, mainly secreted by gastrointestinal G cell. The G cell is atypical open type cell, up to the antrum. As a kind of nutrition gastrointestinal hormone,not only can stimulate the growth of gastrointestinal tract normal mucosa tissue, but canstimulate the gallbladder carcinoma, pancreatic carcinoma, colorectal carcinoma, gastriccarcinoma and other tumor cell growth. At present, most studies showes that gastrin is anautocrine growth factor through the way of autocrine, paracrine, endocrine to achieve itsfunction. Combined with gastrin and its receptor can regulate tumor cells by intracellularsignal transduction pathway of growth, which is combined with the tumor cells producegastrin and its receptor, exert their biological effects. Recently, studies have demonstratedthat the incidence of colorectal cancer related to the abnormal expression of gastrin, somescholars refer to this type of colorectal cancer as hormone-dependent tumors, whichpromotes colon cancer cell proliferation may be through the mechanism by autonomouslygenerating and secreting gastrin and acts on its own receptor on the cell membrane, whichplay a biological effect, but its effects can be inhibited by gastrin receptor antagonist.However, the regulation of molecular mechanism of proliferation in colon cancer remainsunclear.
In recent years, the application of gene chip technology to detect colorectal cancerrelated gene, expressed genes were screened a lot of difference, significant differences ingene expression in many internal and external network, and cell signal transduction pathway is closely related with the inhibition of regulation, directly involved in cellmetabolism, proliferation, differentiation and apoptosis. Protein kinase associated mitogenactivated (mitogen-activated protein kinase, MAPK) signal research attention, MAPK isa intracellular serine/threonine protein kinase, widely present in most mammaliancytoplasm and nucleus, can be the extracellular stimulation signal transduction to the celland its nucleus, and causes cell biological reaction, and regulate of cell proliferation,differentiation, development and apoptosis.MAPK consists of extracellular signal regulatedkinase (ERK), c-Jun N-terminal kinase (JNK)/stress activated protein kinase (SAPK),p38and ERK5/BMK1subgroup MAPK. Multiple signal pathways is made up of thesesubgroups. At present, studies have found that the mammalian cells has three parallelmitogen activated protein kinase pathway. Respectively for the extracellular signalregulated kinase (extracellular-signal regulated protein kinase, ERK) signal pathway, p38MAPK signal pathway, and JNK/SAPK signal pathway. Among them, JNK/SAPK andp38MAPK pathway is related to cellular stress and apoptosis, and ERK pathway is the hubin the MAPK cell signal transduction network is closely related to cell proliferation anddifferentiation. Many studies suggest that MAPK signaling pathway is involved in theregulation of growth of colon cancer cells. Research also found that after combined withgastrin gastrin receptors, through the activation of p38MAPK signaling pathway inducedmRNA and protein expression of urokinase type plasminogen activator (u-PA) expressionenhanced tumor cell invasion, metastasis. Visibly, the MAPK signal transduction pathwayplays an important role in the gastrin-regulated proliferation of colon cancer cells, but themechanism is still unclear.
Therefore we assume that firstly using the ELISA method in79cases of colorectalcancer operation resection specimens for detection of expression of gastrin, screening outthe positive and negative specimens of colorectal carcinoma, and than analyze the positiveexpression rate, pathological type, histological differentiation and clinical staging of Duke's, as to clear the effect of gastrin on colorectal cancer biological characteristics. Secondly,choosing five groups of positive colorectal cancer tissues and adjacent normal mucosa tissue, and another five groups include the negative expression of colorectal carcinoma andthe adjacent normal mucosa, the differential gene expression profiles were analyzed usinggene chip technology, the positive and negative expression groups analysis results werecompared, selected the gene which expression was obvious difference, and selected thesegenes to verify by real-timme PCR. At the same time, all2times more differentiallyexpressed genes input R package, identify differential genes associated with the MAPKsignal transduction pathway. Finally, through the cultivation of human colorectal cancercell line HT-29, usng western blot, RT-PCR technology to detect the differences in geneand protein expression selected in each group respectively which related to signaltransduction pathway of MAPK, and analysed the expression level of gastrin before andafter the impact of its gastrin receptor antagonist proglumide, to explore the molecularmechanisms of gastrin-regulated MAPK signal transduction pathway in large intestinalcancer from the molecular signaling level. To clear the detailed of molecular basis ofgastrin-regulated growth of colorectal cancer from“GAS-MAPK-target genes”signalingpathway, which provide new clues for the effective intervention of the signal transductionpathway links, and for targeted gene therapy provides a new target, and provide atheoretical basis for endocrine therapy of colorectal cancer.
Research was divided into three parts:
PartⅠ: Detection of gastrin expression and analysis of gastrin andbiological behavior of large intestinal cancer
Objective: To explore the rate of positive expression of gastrin in large intestinalcancer, and effects of gastrin on biological characteristics of large intestinal cancer. Suchas pathological type，histological differentiation, clinical staging of Duke 's and so on.
Methods: The protein expression of gastrin was detected on79cases of colorectalcancer operation resection specimens by ELISA and RT-PCR methods. Screening out thepositive and negative of gastrin expression in colorectal cancer tissue specimens. Toanalysis the positive expression rate of gastrin, and effects of gastrin on the extent ofpathological type, tissue differentiation and Duke's staging.
Results: The positive expression rate of GAS mRNA was46.8%in79cases ofcolorectal cancer tissues, and the positive expression rate of GAS protein was40.5%. ThemRNA expression of gastrin is positive correlated with the protein (P<0.01). The mRNAand protein expression of gastrin in poorly differentiated cancers of large intestinal wassignificantly higher than the high and moderate differentiation (P<0.05). The mRNA andprotein expression of gastrin in papillary adenocarcinoma and tubular adenocarcinomawere significantly lower than that in mucinous signet ring cell carcinoma andundifferentiated carcinoma (P<0.05). The mRNA and protein expression of gastrin inDukes A,B were lower than that in Dukes C,D (P<0.05).
Conclusion: There is the expression of gastrin in some of large intestinal carcinoma.Abnormal expression of gastrin is closely related to the extent of tissue differentiation,pathological type and clinical staging of Duke 's. Detection of gastrin can be rection somebiological characteristics of colorectal cancer. Gastrin may be to evaluate target one of thebiological behavior of clinical large intestinal cancer.
PartⅡ:Differential geneScreening of MAPK signal transductionpathway between the positive and negative expression of gastrin in largeintestinal cancer
Objective: To differential gene expression analysis of MAPK signal transductionpathway between the positive and negative expression of gastrin in large intestinal cancer.
Methods: The gene chip technology was used for analyzing the differential geneexpression profiling in the positive expression of gastrin of cancer tissues and normaltissues adjacent to cancer and the gastrin negative expression of cancer tissues and normaltissues adjacent to cancer. The positive and negative sets of results were compared,screening of differentially expressed genes,and the selection of differentially expressedgenes were verified by real-time PCR. At the same time, all2times more differentiallyexpressed genes input R package, identify differential genes associated with the MAPKsignal transduction pathway. Results: Genechip research result showed differential geneincreased more than2times of3529,2times of the down regulated genes were3328 between positive expression of gastrin of cancer tissues and adjacent normal mucosa.Expression of gastrin-negative cancer tissue and adjacent normal mucosa tissue microarrayanalysis showed differential gene increased more than2times with2867,2times of thedown regulated genes were2549. The difference between the two groups of genes withfluorescence cancer marker, and carries on the analysis, analysis of differential gene ofgastrin related results showed differential gene increased more than2times with567,2times of the down regulated genes were342. And screening out related genes of MAPKsignal transduction pathway were78. Respectively, to select up-regulated and downregulated genes were3through gene verification. The analysis results of PCR and the chipwas consistent.
Conclusion: The cDNA microarray method can be used for screening related genesassociated with gastrin in colorectal cancer, the difference of gene differential gene has astrong representation. There are differential genes expression between the positive andnegative expression of gastrin in colorectal carcinoma. MAPK signal transduction pathwayis involved in the gastrin-regulated growth of large intestinal cancer cells.
Part Ⅲ: Role of MAPK signaling pathway in gastrin-regulated cellproliferation and apoptosis of large intestinal cancer and mechanismsstudy
Objective: To explore the relationship between the cells proliferation and apoptosis oflarge intestinal cancer induced by gastrin and signal transduction pathway of MAPK.
Methods: HT-29cells were incubated in the different medium according on differentrequirement.MTT assay investigated the growth change of HT-29cells and determined theoptimal concertration of pentagastrin(PG) and proglumide(PGL) to intervene the cellgrowth. Cells proliferation and apoptosis of HT-29were analyzed with Annexin V-FITCflow cytometry at the optimal concertration of drugs. RT-PCR detected the expression ofgastrin receptor CCK-BR mRNA in HT-29cells and the mRNA expression of ERK1/2,K-ras, p38, bax and bcl-2in each group cells. The protein expression of ERK1/2, K-ras,p38, bax and bcl-2, and ERK1/2, K-ras and p38phosphorylation levels were detected by Western blot.
Results: Gastrin could promote the proliferation of HT-29cells and inhibited cellsapoptosis in a dose dependent manner（6.25-100.00mg/L）,and the optimal concentrationwas25mg/L (P<0.05). Proglumide had no obvious effect on the HT-29cells, but it couldremarkablely inhibit the cells proliferation of gastrin stimulating large intestinal cancer in adose dependent manner(8.00～128.00mg/L), and the optimal dose is32mg/L (P<0.05).The proliferation index(PI) of gastrin group was significantly higher than that of controlgroup and combined treatment group(P<0.01). The apoptotic ratio(AR) of PG group wassignificantly lower than that of control group and combined treatment group(P<0.05).RT-PCR test results showed that there is a clear expression of mRNA about CCK-BR inthe HT-29cells. The mRNA and protein expression of bax and the levels of phosphorylatedp38protein among gastrin group was significantly lower than the control group and thegastrin+proglumid group(P<0.05). On the contrary, the mRNA and protein expression ofbcl-2and the levels of phosphorylated ERK1/2and K-ras protein among gastrin group wassignificantly higher than the control group and the gastrin+proglumidgroup(P<0.05).Compared with gastrin group,the mRNA and protein expression ofERK1/2、K-ras and p38in the other groups have not obviously changed.
Conclusion: Gastrin could promote the human large intestinal cancer cell line HT-29proliferation and inhibit their apoptosis,but which can be restrained by gastrin receptorantagonist proglumide. Gastrin perhaps regulates the cells proliferation and apoptosis oflarge intestinal cancer by signal transduction pathway of ERK-MAPK inRas→Raf→MEK1/2→ERK1/2ways up-regulation ERK1/2and K-ras proteinphosphorylation levels and signal transduction pathway of p38-MAPK inp38MAPK→bcl-2/bax ways down-regulation p38protein phosphorylation levels.
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1. Modlin IM, Kidd M, Marks IN,et al. The pivotal role of John S. Edkins in thediscovery of gastrin. World J Surg,1997;21(2):226-234.
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