摘要
近年来，肿瘤干细胞（cancer stem cells，CSCs；也称肿瘤起始细胞：tumor initiatingcells，TICs）理论认为肿瘤是一个异质性的细胞群体，在这个细胞群体中存在一小部分具有自我更新、多向分化能力的细胞，并且这些细胞具有较强的侵袭、成瘤和耐受放化疗的能力。肿瘤干细胞理论的兴起为我们深入认识肿瘤的发生发展机制并探寻新的治疗靶点开辟了新的途径。本研究主要包括以下两部分内容：
第一部分ATXN1对髓母细胞瘤干性与侵袭特性的调控作用及其分子机制
髓母细胞瘤(medulloblastoma)是儿童最常见的恶性脑肿瘤，临床预后差。我们使用成球培养法从髓母细胞瘤中分离/富集了髓母细胞瘤干细胞，并发现其具有高侵袭性及高成瘤能力的特性。通过本课题组在肺癌和胃癌中对成球细胞与普通贴壁细胞的基因表达谱芯片分析，我们筛选出ATXN1这个差异性表达的基因并发现其在髓母细胞瘤成球细胞中高表达。通过免疫组化染色发现髓母细胞瘤中ATXN1的表达与其临床预后密切相关，因此进一步研究了ATXN1在调控髓母细胞瘤自我更新及侵袭中的作用及可能的分子机制。本部分实验主要方法、研究结果及结论如下：
1、髓母细胞瘤原代细胞的培养及细胞系的建立。
为了更好的了解髓母细胞瘤细胞的生物学特性并满足实验研究的需要，我们收集了5例髓母细胞瘤原代标本进行细胞培养；并且成功建立了一株发生于成人的髓母细胞瘤细胞系。对建系后的细胞采用光镜、电镜、免疫组化、流式细胞术、染色体分析和移植瘤等实验对细胞株生物学特性进行了研究。
2、使用成球培养法成功分离/富集髓母细胞瘤干细胞，并进行了生物学特性鉴定。
（1）用无血清的干细胞培养基对髓母细胞瘤细胞Daoy、ons76和D283培养，三个细胞均能成球生长；（2）实时定量PCR检测发现细胞球细胞（sphere cells, SC）较单层培养细胞（monolayer cell，MN）高表达干性相关基因Bmi1、Nanog、Nestin、Oct4和Sox2及基质金属蛋白酶MMP2、MMP7、MMP9和MMP13；（3）免疫荧光检测表明Daoy-SC高表达Nestin、Sox2和CD133，低表达GFAP、MBP和βⅢ-tubulin；（4）Daoy-SC细胞于含血清的培养基中培养时则高表达GFAP、MBP和βⅢ-tubulin，不表达Nestin、Sox2和CD133；（5）Transwell实验表明Daoy-SC比Daoy-MN具有更强的侵袭能力；（6）裸鼠皮下移植瘤实验表明同数量级的Daoy-SC比Daoy-MN细胞具有更强的肿瘤形成能力。上述结果从干性和侵袭相关基因的表达、多向分化能力、侵袭和成瘤能力等几个方面证实了成球生长的细胞具有TICs的特性。
3、通过基因芯片筛选出在胃癌和肺癌成球细胞中均高表达分子ATXN1，发现ATXN1在调控髓母细胞瘤的迁移、侵袭，自我更新及成瘤能力中均具有重要作用。
（1）实时定量PCR检测发现ATXN1在髓母细胞瘤干细胞中高表达；（2）利用慢病毒干扰Daoy和ons76细胞ATXN1的表达后，可以显著抑制髓母细胞瘤细胞的迁移、侵袭、克隆形成和成瘤能力；（3）过表达ATXN1则增强髓母细胞瘤细胞D283的侵袭和成瘤能力。
4、ATXN1在髓母细胞瘤手术切除标本中的表达情况及其意义。
对262例髓母细胞瘤临床标本进行免疫组化染色，结果显示ATXN1的表达与髓母细胞瘤的病理组织学分型和分子亚型相关。对124例有随访的髓母细胞瘤所做的生存曲线结果显示ATXN1的表达与患者的生存时间成负相关(P=0.0023)，表明ATXN1可以用作判断髓母细胞瘤预后的指标。
5、探讨ATXN1在调控髓母细胞瘤侵袭和自我更新能力方面的可能分子机制。
（1）利用慢病毒干扰Daoy细胞ATXN1的表达后，可以显著抑制髓母细胞瘤干性相关基因Nanog和侵袭相关基因MMP2的表达，同时Hedgehog信号通路的下游关键分子Gli1的表达也明显下调；（2）过表达D283细胞的ATXN1表达后，同样可以增强其干性相关基因Nanog和侵袭相关基因MMP2的表达，并且Gli1的表达也增强；（3）用Hedgehog信号通路的激动剂shh配体及抑制剂环耙明（KAAD-cyclopamin）作用同样可以上调及下调ATXN1的表达，说明ATXN1的表达受Hedgehog信号通路影响；（4）利用siRNA干扰Gli1的表达后可降低Nanog和MMP2的表达，而ATXN1的表达却没不受影响，因而我们推测ATXN1做为Gli1的上游发挥作用，进而影响Nanog和MMP2的表达。
第二部分ALDH1在食管癌干性维持与侵袭中的作用及其分子机制研究
食管鳞状细胞癌（ESCC，Esophageal squamous cell carcinoma）是常见的消化道恶性肿瘤。由于ESCC具有高侵袭及转移的特性因而其预后不佳。而CSC假说则认为肿瘤内的TICs与其它细胞相比具有更强的侵袭和转移能力是造成手术不易彻底切除和术后复发的根源。ESCC中TICs的标志物尚不清楚，而乙醛脱氢酶1（ALDH1，Aldehydedehydrogenase1）是一个与多种肿瘤的TICs功能相关的蛋白质。我们推测ALDH1也可作为人ESCC中TICs的标志物，因而检测了ALDH1在ESCC中的表达及其意义。本部分实验主要方法、研究结果及结论如下：
1、ESCC中ALDH1~(high)的细胞表现出TIC的特征。ALDH1~(high)细胞高表达干性相关基因Sox2和Bmi1，并且ALDH1~(high)比ALDH1low的细胞具有更强的成球能力、平板克隆形成能力和成瘤能力。
2、ALDH1~(high)的细胞具有更强的侵袭和转移能力。体外基质胶侵袭实验及裸鼠尾静脉注射肺转移模型都证实ALDH1~(high)的细胞比ALDH1low的细胞具有更强的侵袭及转移能力。并且ALDH1~(high)的细胞高表达MMP2、 MMP7、MMP9和vimentin,低表达E-cadherin。表明ALDH1~(high)细胞具有EMT表型相关的高侵袭和转移特性。
3、ALDH1的表达与食管的不典型增生和恶性程度相关。ALDH1的表达与病理组织学分级(P=0.004)、浸润深度(P=0.000)、淋巴结转移(P=0.002)和UICC分期(P=0.000)相关。
4、ALDH1的表达与患者的生存期呈显著的负相关，可作为临床预后判断的指标。
Recently, the cancer stem cell (CSC) hypothesis suggests that tumors are organized intoa hierarchy in which only a rare clonal population of cells, termed CSCs or tumor initiatingcells (TICs), have the ability to initiate, proliferate, and maintain tumor growth. Emerging ofCSCs hypothesis provides us a new way insight into the mechanism underlining tumorinitiation and progression. This article included two parts as follows:
PartⅠ: The role and correlated molecular mechanisms of ATXN1in stemness andinvasion of medulloblastoma.
Medulloblastoma is the most common malignant brain tumor in children. Despite recentimprovements in cure rates, survivors suffer from serious therapy-related side-effects. Manysurviving children have long-term cognitive and/or neuroendocrine adverse effects. Todemonstrate the existence of medulloblastoma TICs (MTICs) and explore their malignantbehavior, we established a method of sphere forming culture to gain the tumor spheres frommedulloblastoma cell lines. Tumor sphere cells possessed multi-potent differentiation ability,highly invasion and tumorigenicity, indicating that tumor spheres enriched MTICs.
Ataxin1(ATXN1) is a polyglutamine protein of unknown function, whose mutant formcauses spinocerebellar ataxia type1(SCA1). ATXN1over-expressed in both lung cancer andgastric cancer stem cells, was also found over-expressed in MTICs. Then, the roles andcorrelated molecular mechanisms of ATXN1in stemness and invasion of medulloblastomawere explored. Main methods, results and conclusions of this part as follows:
1. The primary culture and establishment of medulloblastoma cell line from Chineseadult patients. For better comprehend the biologic traits of medulloblastoma and satisfy theneeds of experimental research, five cases of medulloblastoma specimen were collected andproceed cell culture. Fortunately, one primary medulloblastoma cell line was successfully established. Light microscopy, electro microscopy, immunohistochemistry, flow cytometry,karyotype analysis and tumor implantation experiments were carried out to characterize thebiological behaviors.
2. Tumor spheres formed from medulloblastoma possess stem cell properties.(1)medulloblastoma cell lines of Daoy, ons76and D283could grow as tumor sphere in serumfree conditioned medium.(2) Compared with monolayer cells (MN), sphere cells (SC) highlyexpressed stemness-related genes Bmi1, Nanog, Nestin, Oct4and Sox2. Invasion-relatedgenes MMP2, MMP7, MMP9and MMP13were all over-expressed in SC compared to MN.(3) Immunofluorescence staining results indicated that Daoy-SC with increased-expression ofstemness-related protein Nestin, Sox2and CD133, decreased expression of differentiatedmarker GFAP, MBP and βⅢ-tubulin.(4) Cultured Daoy-SC in medium supplemented with10%FBS, the cells could be induced to express GFAP, MBP and βⅢ-tubulin positive cells.(5)Transwell matrigel invasion assay was performed to assess the invasion capacity, we foundthat indicating Daoy-SC possess higher invasion capacity compare to Daoy-MN.(6)Xenograft assay showed that Daoy-SC were highly tumorigenic. Those data suggested thatsphere cells possess stem cell properties.
3. Our results demonstrated that ATXN1plays an important role in immigration, invasion,self-renewal and tumorigenesis in medulloblastoma.(1) ATXN1was found highly expressedin MTICs by real time PCR and Western blot.(2) Silenced ATXN1expression inmedulloblastoma cells by shRNA, the abilities of sphere formation, invasion andtumorigenesis were impaired.(3) Over-expressing ATXN1, the abilities of invasion andtumorigenesis of D283cells were increased.
4. ATXN1expression has important clinical significance in patients withmedulloblastoma. Immunohistochemistry (IHC) was used to detect the expression of ATXN1in262specimens of medulloblastoma, the result showed that the expression of ATXN1wascorrelated with histological subtypes and molecular subgroups. Patients with lower ATXN1expression had longer overall survival time than higher ones (P=0.0023), indicating thatATXN1is an indicator of poor prognosis in medulloblastoma.
5. The possible molecular mechanisms of ATXN1in invasion and self-renewal abilitiesof medulloblastoma cells were explored.(1) Silenced ATXN1expression in Daoy cells byshRNA, the expression of stemness-related gene Nanog and invasion-related gene MMP2 were down-regulated, meanwhile, Gli1, the key molecular of Hh signal pathway, wasdown-regulated significantly.(2) Overexpressed ATXN1in D283cells, Nanog, MMP2andGli1were all up-regulated significantly.(3) The Shh ligand and KAAD-cyclopamine couldstimulate or inhibit the expression of Gli1and ATXN1in Daoy cells. These results imply thepresence of a positive loop between ATXN1and Gli1.(4) Silencing Gli1expression bysiRNA resulted in decreased expression of Nanog and Gli1, but expression of ATXN1was notinfluenced, so we supposed ATXN1might be an upstream factor of Gli1to exert effect.
PartⅡ: ALDH1plays important roles in esophageal squamous cell carcinoma(ESCC) stemness maintenance, invasion and metastasis.
ESCC is one of the most frequent fatal malignancies. The five year survival rate ofESCCs after surgery and chemotherapy remains low due to highly invasive and metastaticnature of ESCC. Recent studies suggest that TICs are responsible for invasion andmetastasis of many tumor types. Therefore the biomarkers related to invasion and metastasisof TICs need to be identified in ESCC.
Aldehyde dehydrogenase1(ALDH1) is a TIC-associated protein in various malignanttumors and its level correlates with the patient outcome. We hypothesize that ALDH1mayalso be used to detect and enrich TICs and the level of ALDH1~(high)cells in tumor may predictthe prognosis of human ESCC. Main methods, results and conclusions of this part as follows:
1. ALDH1~(high)ESCC cells exhibited TICs properties. We examined the proportion ofALDH1~(high)cells contained in ESCC cell line EC109, and found that the sorted ALDH1~(high)cells possessed higher capabilities of tumor sphere formation as well as colonies formationas compared to ALDH1lowones. The ALDH1~(high)cells also showed increased expression ofthe stemness genes Sox2and Bmi1and higher tumorgenecity compred to ALDH1lowcells.
2. ALDH1~(high)cells possessed highly invasive and metastatic capabilities with EMTphenotype. Matrigel invasion assay indicated that ALDH1~(high)cells had a greaterinvasiveness as compared to ALDH1lowones. Moreover, the ALDH1~(high)cells formed lungmetastasis in five of six (5/6) mice, whereas no metastasis was found by the ALDH1lowones.Gene expression analysis further showed that the ALDH1~(high)cells expressed higher levelsof matrix metalloproteinase (MMP)-2,-7,-9and vimentin, and lower level of E-cadherin,indicating their highly invasive and metastatic capabilities related to EMT phenotype.
3. ALDH1expression was correlated with esophageal dysplasia and ESCC malignancy. ALDH1was not detected in normal esophageal epithelia, but detectable in the dysplasticbasal cells to some extents. Furthermore, the cytoplasmic ALDH1was elevated in theexpression levels along with the increasing grades of dysplasia and the formation ofcarcinoma in situ. The expression of ALDH1was positively correlated with histologicalgrade (P=0.004), invasion depth (P=0.000), lymph node metastasis (P=0.002) andUICC stage (P=0.000) of ESCCs.
4. ALDH1is associated with ESCC outcome and can be used as a biomarker forpatient prognosis.
引文
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