發(fā)布時(shí)間：2018-05-03 19:25

  本文選題：Ski + Smad3/2�。� 參考：《第三軍醫(yī)大學(xué)》2011年博士論文

【摘要】：細(xì)胞增殖是生命的基本特征,不但參與個(gè)體的發(fā)育、機(jī)體的修復(fù)等生理過(guò)程,而且參與難愈、瘢痕形成、腫瘤發(fā)生等病理過(guò)程。因此,合理調(diào)控細(xì)胞增殖,不僅有利于促進(jìn)組織修復(fù),而且對(duì)提高修復(fù)質(zhì)量,抑制瘢痕乃至腫瘤形成具有重要意義。創(chuàng)傷愈合發(fā)生率極高,且緩慢的愈合過(guò)程和不良的愈合結(jié)果(例如增生性瘢痕和瘢痕疙瘩)是人類(lèi)創(chuàng)傷愈合領(lǐng)域所面臨的兩大難題。盡管目前促進(jìn)創(chuàng)傷愈合和抑制過(guò)度瘢痕形成的治療方法有很多,但是,在促愈和瘢痕治療之間還存在著一定的矛盾:如生長(zhǎng)因子類(lèi)促愈治療的同時(shí)具有加重瘢痕形成的風(fēng)險(xiǎn);對(duì)于瘢痕的治療目前主要依賴(lài)經(jīng)驗(yàn)性治療,且治療效果不好,有的副作用大甚至影響愈合。另外,由于存在創(chuàng)傷后創(chuàng)面受體表達(dá)容易發(fā)生缺乏及變異、創(chuàng)面局部蛋白酶濃度升高、蛋白酶和其抑制因子比例失衡等因素,使受體類(lèi)治療途徑難以達(dá)到理想促愈效果。因此,尋求新的非受體作用途徑的促增殖劑,對(duì)促進(jìn)創(chuàng)傷愈合尤其是放創(chuàng)復(fù)合傷、大面積創(chuàng)傷、燒傷等難愈傷口有著十分重要的意義。 c-Ski作為一種鳥(niǎo)類(lèi)癌基因v-ski的細(xì)胞內(nèi)同源物蛋白,在各種動(dòng)物中有較高的同源性,在人體中稱(chēng)之為Ski。Ski在不同類(lèi)型的組織和細(xì)胞中分布廣泛,不僅可以抑制Smad3/2活性,還可調(diào)節(jié)多種核因子的轉(zhuǎn)錄活性,如促進(jìn)NFI(促核因子I)的轉(zhuǎn)錄、抑制癌基因Rb的轉(zhuǎn)錄等,從而參與神經(jīng)系統(tǒng)發(fā)育、造血細(xì)胞的增殖和分化、腫瘤發(fā)生、組織再生等多種生理、病理過(guò)程。我們前期研究發(fā)現(xiàn)Ski是一創(chuàng)傷修復(fù)相關(guān)基因,繼而,在大鼠切割傷模型上的轉(zhuǎn)基因?qū)嶒?yàn)證實(shí)Ski具有在促愈的同時(shí)減輕瘢痕形成的雙重作用,并在兔耳增生瘢痕模型上得到了驗(yàn)證。并且Ski表現(xiàn)出比現(xiàn)有促愈措施或抗瘢痕方法更好的效果,這不僅為同時(shí)實(shí)現(xiàn)促進(jìn)創(chuàng)傷愈合和抑制瘢痕形成這看似矛盾的效應(yīng)成為可能,而且提示Ski可能是一個(gè)具有治療難愈性傷口和增生性瘢痕的臨床應(yīng)用前景的分子。 已有文獻(xiàn)及前期研究表明Ski可能是一個(gè)細(xì)胞增殖的調(diào)節(jié)因子,并具有促進(jìn)愈合和減輕瘢痕的雙重作用,但是,其在細(xì)胞增殖、創(chuàng)傷愈合及瘢痕形成中的作用機(jī)制還不清楚,尤其,作為原癌基因的Ski在多種人類(lèi)惡性腫瘤中顯著表達(dá),在這種細(xì)胞無(wú)限增殖病理過(guò)程中作用如何所知不多,不但影響其生物學(xué)效應(yīng)的闡明,也嚴(yán)重制約了其在創(chuàng)傷治療中的應(yīng)用前景。不過(guò),已有研究表明Smad3具有抑制細(xì)胞增殖的作用,表明抑制Smad3可具有促進(jìn)增殖作用;同時(shí),1999年美國(guó)NIH小組首次報(bào)道,Smad3基因敲除小鼠的傷口愈合速率增加了2倍,這一結(jié)果證實(shí)了抑制Smad3具有促愈作用;另外,近些年研究表明TGF-beta信號(hào)系統(tǒng)尤其是Smad3/2信號(hào)因子(他們轉(zhuǎn)導(dǎo)的信號(hào)系統(tǒng)也稱(chēng)為T(mén)GF-β1/Smad依賴(lài)途徑)高活性是導(dǎo)致瘢痕形成的重要原因,因此,抑制Smad3/2成為了減輕瘢痕形成的新途徑。而且,TGF-β1/Smad依賴(lài)途徑抑制細(xì)胞增殖作用從而使TGF-β1具有抗腫瘤發(fā)生作用,此途徑的功能障礙被認(rèn)為是TGF-β1抗腫瘤作用喪失的原因。這些都提示Ski基因作為Smad3、Smad2的輔阻遏子,其可能通過(guò)調(diào)節(jié)Smad3/2而在促進(jìn)增殖、傷口愈合、瘢痕形成甚至腫瘤發(fā)生等方面發(fā)揮作用,是否如此需要進(jìn)一步的證實(shí)。 為此,本課題在前期研究的基礎(chǔ)上,分三個(gè)部分進(jìn)行如下研究:(1)Ski在細(xì)胞增殖及TGF-β1調(diào)節(jié)增殖中的作用研究:本部分研究采用原代成纖維細(xì)胞(Fibroblast,FB)和纖維肉瘤細(xì)胞(L929),通過(guò)體外實(shí)驗(yàn),在明確TGF-β1對(duì)FB和L929增殖調(diào)節(jié)作用不同的基礎(chǔ)上,利用RNAi干擾c-Ski后結(jié)合TGF-β1刺激來(lái)驗(yàn)證Ski在其調(diào)節(jié)增殖中所發(fā)揮的作用,并探討其促進(jìn)增殖的機(jī)理是否與其抑制Smad3/2有關(guān);進(jìn)一步,采用纖維肉瘤細(xì)胞移植瘤模型,對(duì)TGF-β1通過(guò)調(diào)節(jié)Ski來(lái)促進(jìn)腫瘤生長(zhǎng)進(jìn)行驗(yàn)證;(2)Ski在創(chuàng)傷愈合中的雙重作用和機(jī)理研究:首先,采用大鼠創(chuàng)傷及兔耳增生性瘢痕模型來(lái)觀察Ski促愈和減輕瘢痕的雙重作用,并采用RNAi干擾質(zhì)粒局部皮下注射來(lái)驗(yàn)證Ski雙重作用的特異性;進(jìn)一步,利用Ski裸質(zhì)粒治療大鼠創(chuàng)傷愈合模型,探討Ski雙重作用的分子機(jī)制是否與調(diào)節(jié)TGF-β1/Smad依賴(lài)途徑有關(guān);(3)Ski及TGF-β1/Smad依賴(lài)途徑相關(guān)信號(hào)因子在人體增生性瘢痕中的表達(dá)觀察:利用收集的人體瘢痕標(biāo)本來(lái)檢測(cè)Ski及其相關(guān)調(diào)節(jié)因子的表達(dá)規(guī)律,以此探討Ski在人體增生性瘢痕中的表達(dá)及與TGF-β1/Smad依賴(lài)途徑的關(guān)系。主要結(jié)果與結(jié)論如下: 1.在前期發(fā)現(xiàn)c-Ski參與TGF-β1雙向調(diào)節(jié)FB細(xì)胞增殖變化作用的基礎(chǔ)上,本研 究采用體外細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn),c-Ski在L929細(xì)胞中持續(xù)高表達(dá)與TGF-β1對(duì)FB和L929的增殖調(diào)節(jié)存在著雙向到單向的轉(zhuǎn)變有關(guān),并在動(dòng)物移植瘤實(shí)驗(yàn)中證實(shí)高表達(dá)的c-Ski促進(jìn)移植瘤持續(xù)生長(zhǎng);此外,實(shí)驗(yàn)發(fā)現(xiàn)與FB不同的是,L929細(xì)胞自分泌及移植瘤組織中的TGF-β1濃度持續(xù)增高。上述結(jié)果提示c-Ski是重要的細(xì)胞增殖調(diào)節(jié)因子,且其持續(xù)、過(guò)高表達(dá)可能是L929腫瘤細(xì)胞持續(xù)增殖的重要原因,而L929腫瘤細(xì)胞分泌高濃度TGF-β1是其發(fā)揮持續(xù)增殖作用的基礎(chǔ)。Ski的這一重要作用可能是創(chuàng)傷后細(xì)胞增殖在創(chuàng)傷修復(fù)完成后能自動(dòng)停止而腫瘤細(xì)胞不能停止的機(jī)制之一。 2.前期實(shí)驗(yàn)發(fā)現(xiàn)c-Ski的低表達(dá)增強(qiáng)Smad信號(hào)而c-Ski高表達(dá)抑制Smad信號(hào)是高低濃度TGF-β1不同調(diào)節(jié)細(xì)胞增殖作用不同的原因。本研究通過(guò)L929細(xì)胞體外實(shí)驗(yàn)發(fā)現(xiàn),高表達(dá)的Ski雖然沒(méi)有改變Smad2/3的磷酸化水平,但可顯著抑制其下游信號(hào)因子P21的表達(dá)水平,提示高表達(dá)的c-Ski可通過(guò)調(diào)節(jié)Smad途徑參與TGF-β1的單向促進(jìn)L929增殖作用;不過(guò),實(shí)驗(yàn)中還發(fā)現(xiàn)低濃度TGF-β1刺激24小時(shí)后,c-Ski表達(dá)水平增高但P21表達(dá)水平無(wú)明顯變化,而細(xì)胞增殖仍舊增高,提示高表達(dá)的c-Ski促進(jìn)L929增殖作用存在調(diào)節(jié)非Smad途徑的可能。上述結(jié)果不僅表明c-Ski調(diào)節(jié)增殖作用的分子機(jī)制與抑制Smad信號(hào)系統(tǒng)有關(guān),而且為其能通過(guò)調(diào)節(jié)細(xì)胞增殖而參與調(diào)節(jié)愈合奠定基礎(chǔ)。 3.細(xì)胞研究發(fā)現(xiàn)Ski不但具有促增殖作用還有調(diào)節(jié)成纖維細(xì)胞向肌成纖維細(xì)胞轉(zhuǎn)化和膠原分泌等作用。本實(shí)驗(yàn)通過(guò)對(duì)人體瘢痕標(biāo)本的檢測(cè),發(fā)現(xiàn)在病理性瘢痕中Ski表達(dá)相對(duì)較低而TGF-β1/Smad信號(hào)系統(tǒng)高表達(dá),這不但為確定Ski在瘢痕形成中的作用提供了線(xiàn)索,也進(jìn)一步驗(yàn)證了TGF-β1/Smad信號(hào)系統(tǒng)在病理性瘢痕中的促進(jìn)作用。結(jié)合前期轉(zhuǎn)染Ski實(shí)驗(yàn)可逆轉(zhuǎn)Smad3對(duì)成纖維細(xì)胞的促膠原分泌和抑制組織Smad信號(hào)及瘢痕形成的結(jié)果,表明低表達(dá)的Ski降低了對(duì)TGF-β1/Smad信號(hào)系統(tǒng)的抑制是病理性瘢痕形成的原因之一,這為今后Ski在瘢痕形成中的作用及機(jī)制研究提供了有用的線(xiàn)索。 4.前期通過(guò)轉(zhuǎn)ski基因?qū)嶒?yàn)在大鼠創(chuàng)傷模型中發(fā)現(xiàn)Ski具有促愈和減輕瘢痕形成的雙重作用,且在兔耳增生性瘢痕模型上也取得同樣的結(jié)果。本研究采用RNAi方法在大鼠創(chuàng)傷模型中發(fā)現(xiàn)干擾不僅顯著降低Ski表達(dá)水平,同時(shí)傷口愈合減慢和愈后瘢痕面積增大,這反向確認(rèn)了Ski雙重作用來(lái)自于其本身。這不僅使同時(shí)實(shí)現(xiàn)促進(jìn)創(chuàng)傷愈合和抑制瘢痕形成這看似矛盾的效應(yīng)成為可能,也為創(chuàng)傷愈合和瘢痕的早期干預(yù)性治療提供了新的思路。 5.大鼠創(chuàng)傷模型愈合過(guò)程的病理學(xué)及免疫組化分析結(jié)果表明,新生上皮中c-Ski表達(dá)增高,且轉(zhuǎn)ski基因使其表達(dá)進(jìn)一步提高的同時(shí)使新生上皮明顯增多、爬行更遠(yuǎn);轉(zhuǎn)ski基因側(cè)肉芽組織增多,Cyclin D和Col l表達(dá)增高且與Ski表達(dá)增高一致;另外,轉(zhuǎn)ski基因側(cè)創(chuàng)面內(nèi)CD11b(代表粒細(xì)胞和巨噬細(xì)胞等炎性細(xì)胞標(biāo)志)陽(yáng)性細(xì)胞減少。上述結(jié)果提示轉(zhuǎn)ski基因除調(diào)節(jié)增殖作用外,還可可通過(guò)減輕炎癥反應(yīng)、加快上皮化、增加肉芽形成而達(dá)到促進(jìn)愈合作用。 6.大鼠創(chuàng)傷模型愈后瘢痕的病理學(xué)及免疫組化分析結(jié)果表明,轉(zhuǎn)ski基因側(cè)膠原排布似網(wǎng)狀,瘢痕膠原成熟度高更接近正常皮下膠原,而且α-SMA陽(yáng)性細(xì)胞減少、Col l表達(dá)降低,提示轉(zhuǎn)ski基因可通過(guò)減少膠原沉積和加快瘢痕組織重構(gòu)而達(dá)到抑制瘢痕形成作用。 7.大鼠創(chuàng)傷模型的分子檢測(cè)結(jié)果表明,轉(zhuǎn)ski基因抑制了Smad3/2的磷酸化水平及其下游信號(hào)因子P21的表達(dá)水平,提示Ski雙重作用的分子機(jī)制與Smad依賴(lài)途徑相關(guān);另一方面,Smad3/2表達(dá)及其磷酸化水平在愈合后期增高,且愈合早期膠原合成增高,則提示Ski雙重作用的分子機(jī)制存在調(diào)節(jié)非Smad依賴(lài)途徑的可能,這可能是我們今后繼續(xù)研究的重點(diǎn)和進(jìn)一步闡明Ski雙重作用分子機(jī)制的關(guān)鍵。
[Abstract]:Cell proliferation is the basic characteristic of life. It not only participates in the physiological processes of individual development, body repair and other physiological processes, but also participates in the pathological processes such as hard healing, scar formation and tumor occurrence. Therefore, the rational regulation of cell proliferation is beneficial not only to the promotion of tissue repair, but also to the improvement of the quality of repair and the formation of scar and even the formation of tumor. The high incidence of wound healing, the slow healing process and poor healing results, such as hypertrophic scars and keloids, are the two major challenges in the field of human healing. Although there are many treatments to promote wound healing and inhibit hypertrophic scar formation, there is still a presence between healing and scar therapy. Certain contradictions: for example, growth factor therapy has the risk of aggravating scar formation while the treatment of scar is mainly dependent on empirical treatment, and the treatment effect is not good, some side effects may even affect healing. In addition, due to the lack and variation of the expression of the wound receptor, the local protease in the wound surface is easy to occur. The increase in concentration and the imbalance of the proportion of protease and its inhibitory factors make it difficult for the receptor therapy pathway to achieve the ideal healing effect. Therefore, it is of great significance to seek a new non receptor pathway to promote the healing of wound healing, especially wound healing, trauma, and burn wounds.
C-Ski, as an intracellular homologous protein of avian oncogene v-Ski, has high homology in various animals. It is called Ski.Ski in different types of tissues and cells. It not only inhibits Smad3/2 activity, but also regulates the transcriptional activity of many kinds of nuclear factors, such as promoting the transcription of NFI (nuclear factor I) and inhibiting the transcription of NFI (nuclear factor I). The transcription of the oncogene Rb and so on, thus participating in the development of the nervous system, the proliferation and differentiation of the hematopoietic cells, the occurrence of tumor and the tissue regeneration, and other physiological and pathological processes. Our previous study found that Ski is a wound repair related gene, and then the transgenic experiment on the rat model of cutting injury confirmed that Ski has the reduction of scar while reducing the scar while reducing the scar. The dual effect of the formation is verified in the rabbit ear hypertrophic scar model. And Ski shows a better effect than the existing healing measures or anti scar methods. This is not only possible to achieve the paradoxical effect of promoting wound healing and inhibiting scar formation at the same time, but also suggests that Ski may be a refractory injury. Molecular markers for the clinical application of oral and hypertrophic scars.
The previous literature and previous studies have shown that Ski may be a regulator of cell proliferation and has the dual role of promoting healing and reducing scar. However, the mechanism of its role in cell proliferation, wound healing and scar formation is not clear, especially, as the proto oncogene Ski is expressed in a variety of human malignant tumors, in this case The role of cell unlimited proliferation in the pathological process is not well known, which not only affects the explanation of its biological effects, but also seriously restricts its application in the treatment of trauma. However, some studies have shown that Smad3 has the effect of inhibiting cell proliferation, indicating that inhibition of Smad3 can promote proliferation. At the same time, the United States NIH team in 1999 was the first It is reported that the rate of wound healing in Smad3 knockout mice increased by 2 times, and this result confirmed that inhibition of Smad3 has a promoting effect. In addition, recent studies have shown that the high activity of the TGF-beta signal system, especially the Smad3/2 signal factor, which is also called the TGF- beta 1/Smad dependent pathway, is an important cause of scar formation. Therefore, inhibition of Smad3/2 has become a new way to reduce scar formation. Furthermore, the TGF- beta 1/Smad dependent pathway inhibits cell proliferation and makes TGF- beta 1 antitumor. The dysfunction of this pathway is considered to be the cause of the loss of TGF- beta 1. These suggest that the Ski gene is a repressor of Smad3, Smad2, and it can be used as a repressor. Whether Smad3/2 can play a role in promoting proliferation, wound healing, scarring and even tumor formation can be further verified.
To this end, on the basis of previous research, three parts are studied as follows: (1) the role of Ski in cell proliferation and TGF- beta 1 regulation of proliferation: this part studies the use of primary fibroblasts (Fibroblast, FB) and fibrosarcoma cells (L929). Through in vitro experiments, the regulation of TGF- beta 1 on the proliferation of FB and L929 is different. On the basis of RNAi interference c-Ski and TGF- beta 1 stimulation to verify the role of Ski in its regulation and proliferation, and to explore whether its mechanism of promoting proliferation is related to its inhibition of Smad3/2; further, the fibrosarcoma cell transplantation tumor model is used to verify the growth of the tumor by regulating Ski to promote the growth of the tumor; (2) Ski in the wound healing. The double role and mechanism of the combination: first, the double effects of Ski promoting and reducing scar were observed by rat trauma and rabbit ear hypertrophic scar model, and the specificity of Ski double action was verified by RNAi interfering plasmids. Further, Ski naked plasmids were used to treat the wound healing model of rats, and the double action of Ski was discussed. Whether the molecular mechanism is related to the regulation of TGF- beta 1/Smad dependence; (3) the expression of Ski and TGF- beta 1/Smad dependent signaling factors in human hypertrophic scars: to detect the expression of Ski and its related regulatory factors by using collected human cicatricial specimens to explore the expression of Ski in human hypertrophic scars and the expression of Ski in human hypertrophic scars. The main results and conclusions are as follows: TGF- 1/Smad dependent pathway.
1. in the early stage, we found that c-Ski participates in the two-way regulation of FB cell proliferation by TGF- beta 1.
In vitro cell test, the persistent high expression of c-Ski in L929 cells was related to the bidirectional to unidirectional transformation of TGF- beta 1 to the proliferation regulation of FB and L929. In the animal transplantation tumor experiment, the high expression of c-Ski promoted the sustained growth of the transplanted tumor. In addition, the experiment found that the L929 cell autocrine and the transplant tumor group were different from the FB. The concentration of TGF- beta 1 in the fabric continues to increase. These results suggest that c-Ski is an important cell proliferation regulator, and its persistence, high expression may be an important reason for the sustained proliferation of L929 tumor cells, and the secretion of high concentration of TGF- beta 1 from L929 tumor cells is the important role of the basal.Ski for its continuous proliferation. Cell proliferation is one of the mechanisms by which cell proliferation can stop automatically and the tumor cells can not stop after wound healing.
2. earlier experiments found that the low expression of c-Ski enhanced the Smad signal and the high expression of c-Ski was the reason for the different proliferation of TGF- beta 1 cells with high and low concentration. This study found that the high expressed Ski could inhibit the downstream signal factor P21 significantly, although the high expressed Ski did not change the phosphorylation of Smad2/3. The expression level suggested that high expression of c-Ski could contribute to the proliferation of L929 by regulating Smad pathway in TGF- beta 1. However, in the experiment, the expression level of c-Ski was increased but the expression level of P21 was not obviously changed after 24 hours of low concentration of TGF- beta 1, but the proliferation of cells was still higher, suggesting that the high expression of c-Ski promoted the effect of L929 proliferation. It is possible to regulate the non Smad pathway. These results not only indicate that the molecular mechanism of the proliferation of c-Ski is related to the inhibition of the Smad signal system, but also lays the foundation for its involvement in regulating the healing of cells by regulating cell proliferation.
The 3. cell study found that Ski not only promotes proliferation but also regulates the transformation of fibroblasts into myofibroblast and collagen secretion. This experiment shows that the expression of Ski is relatively low in pathological scars and high expression of TGF- beta 1/Smad signal system in pathological scars, which not only determines the formation of Ski in scar formation. The effect of TGF- beta 1/Smad signaling system in pathological scar was further verified. Ski experiment combined with pre transfection could reverse the collagen secretion of Smad3 and inhibit the formation of Smad signal and scar formation of tissue, indicating that low expression of Ski reduced the inhibition of TGF- beta 1/Smad signal system. It is one of the causes of pathological scar formation, which provides a useful clue for the research of the role and mechanism of Ski in scar formation in the future.
4. in the early stage of the ski gene experiment, we found that Ski had double effects on promoting and alleviating scar formation in the rat model, and the same results were obtained in the rabbit ear hypertrophic scar model. This study found that interference not only significantly reduced the level of Ski expression, but also slowed the healing of wound healing in the rat model of traumatic hypertrophic scar. The increase in scar area, which confirms that the double effect of Ski comes from itself, not only makes it possible to realize the paradoxical effect of promoting wound healing and inhibiting scar formation, but also provides new ideas for the early intervention treatment of wound healing and scar.
The pathological and immunohistochemical results of the healing process of the 5. rat models showed that the expression of c-Ski in the newborn epithelium was increased, and the expression of ski gene was increased and the expression of the new epithelium was increased, and the ski gene lateral granulation tissue was increased, the expression of Cyclin D and Col l increased and the expression of Ski was increased and the expression of Ski was higher. The positive cells of CD11b (the inflammatory cell markers such as granulocyte and macrophage) in the ski gene side were reduced. The results suggested that the transfer of ski gene, in addition to the regulation of proliferation, also accelerated the epithelialization by alleviating the inflammatory response, and increased the formation of granulation to promote the more cooperative use.
The pathological and immunohistochemical results of the healing scar of the 6. rat models showed that the reticular formation of the ski gene was similar to the normal subcutaneous collagen, and the -SMA positive cells decreased and the expression of Col l decreased. It suggested that the transfer of ski gene could be achieved by reducing the deposition of collagen and accelerating the reconstruction of scar tissue. Inhibition of scar formation.
The molecular detection results of the 7. rat models showed that the ski gene inhibited the phosphorylation level of Smad3/2 and the expression level of the downstream signal factor P21, suggesting that the molecular mechanism of the double action of Ski was related to the Smad dependent pathway; on the other hand, the expression of Smad3/2 and its phosphorylation were increased at the later stage of healing, and the collagen synthesis was increased at the early stage of healing. It is suggested that the molecular mechanism of the double action of Ski has the possibility of regulating non Smad dependence, which may be the key to further study and further clarify the mechanism of Ski double action.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類(lèi)號(hào)】：R363

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本文編號(hào)：1839772