宫颈癌干细胞表面标记物的筛选及Bcrp1~+表型HeLa细胞生物学功能的鉴定
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摘要
为研究宫颈癌发病机制及放化疗抵抗机理,为宫颈癌以肿瘤干细胞为标靶进行治疗提供线索,本研究通过体内、外试验分别对宫颈癌组织标本及宫颈癌细胞株(Hela细胞)进行宫颈癌干细胞标记物的筛选及鉴定,并对Hela细胞中的Bcrpl~+亚群细胞的生物学特征及相关功能进行检测。结果发现:在宫颈癌组织中,CK17表达于侵袭前沿,其表达强度和表达率与肿瘤的恶性程度及转移相关;Bcrpl在化疗后表达增强,并与肿瘤的恶性程度相关;CD44v5只在少量宫颈癌细胞的胞膜上表达,无规律性。在宫颈癌细胞株Hela细胞中,CK17、CD44v5及Bcrpl均有表达;采用流式分选后发现,在Bcrpl~+群当中含有绝对优势量的CK17和CD44v5阳性细胞。进一步的研究证实Bcrpl~+群细胞虽然含量较少,但却具有较强的生长活力、抗凋亡能力、抗放化疗能力及侵袭力,是一组具备干细胞特征的细胞群,其中可能含有宫颈癌干细胞。
本研究结合目前肿瘤干细胞的研究成果,对可能成为宫颈癌干细胞的标记物进行筛选,率先对Hela细胞中的Bcrpl~+亚群细胞进行了功能鉴定,由此推测Bcrpl~+可能成为宫颈癌干细胞标记物,丰富了实体肿瘤干细胞的研究,并为宫颈癌耐药机制的研究及多靶点药物治疗提供了全新的理论线索和支持。
[Object]One view of cancer is that it may arise from a single cell that has the ability to self-renew and thus to maintain the growth of a tumor,whereas the majority of its cellular progeny does not.A considerable effort is going into determining unique properties of these cells,because such cells might be expected to share properties with adult stem cells in normal tissues,they are often termed cancer stem cells.There is increasing evidence that cancers might contain their own stem cells.Many cancers, like normal organs,seem to be maintained by a hierarchical organization that includes slowly dividing stem cells,rapidly dividing transit amplifying cells(precursor cells), and differentiated cells.The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology.The presence of a small subpopulation of slowly dividing cancer stem cells might explain why so many cancers recur after treatment with irradiation or cytotoxic drugs,even when most of the cancer cells seem to be killed by the therapy.Usually,some cancer cells survive the treatment,and these surviving cells may be cancer stem cells,which may be not only resistant to the therapy but also essential for the malignancy of the cancer.However,in spite of old and more recent evidence that cancer stem cells exist,there is still a dearth of good phenotypic markers for such cells.In addition,many of the self-renewing cancer cell populations that are studied may also contain early progenitor cells that are derived from cancer stem cells but are also able to initiate and maintain tumor growth.Therefore,we join others to do some research about phenotypic markers for cervical caner stem cells.
Cervical cancer is a disease that results in devastating mortality,especially in developing countries,and it is the leading cause of cancer mortality and the second most common type of cancer in women worldwide after breast cancer.With the development of CSC theory,more and more gynecologists do a lot of research about cervical cancer stem cells,but non of them succeed.Because cervical cancer cells is difficult to be isolated from cervical tissues and there is also lack of classical markers of cervical stem cells.So it is the key point to find the cervical cancer stem cells.According to the researches about the CSC and cervical reserve cells,we choose CK17,CD44v5,P63,Bcrp1 as markers and investigate the expression of CK17, CD44v5,P63,Bcrp1 in cervical cancer tissue and HeLa cell line.We also identify the Characterization of Bcrp 1~+ HeLa cells.
[Methods and results]
1 The expression of CK17,CD44v5,P63 and Bcrp1 in normal cervical tissue and cervical squamous cancer specimens.
We investigated a total 75 specimens:cervical squamous cancer(n=55),normal cervix(n=20).All cases were analysed immunohistochemically using antibodies against CK17,CD44v5,P63 and Bcrp1.The results as follow:
(1) CK17 is expressed in reserve cells cytoplasm in normal cervical specimens.The expression were increased in cervical squamous cancer specimens. And with the metastatic,the expression of CK17 is increased and it seems that CK17 is stained in the margin of the cancer nest and the tumor embolus.In specimens with high grade malignant cancer or after the chemotherapy,the expression of CK17 is increased.
(2) p63 is stained in nuclei of reserve cells and almost all cancer cells.
(3) CD44v5 is stained in reserve cells and a part of cancer cells membranes.The expression is increased in cervical squamous cancer specimens.But the expression of CD44v5 is irregularly and the it is not increased as much as others markers.
(4) Bcrp1 is stained in reserve cells and a part of cancer cells membranes.In specimens with high grade malignant cancer or after chemotherapy,the expression of Bcrp1 is increased too.
(5) The result of double immunohistochemical examination show us that almost all cells which express CK17 are also express Bcrpl,but not all cells which express Bcrpl are express CK17.
2 The isolation of CK17~+,CD44v5~+and Bcrp1~+ cell in Hela cell line
We use flow Cytometry to identify and isolate the CK17~+,CD44v5~+ and Bcrp1~+ cells in Hela cell line.Result:
(1) Hela cells contained 0.7%CK17~+ cells,0,1%CD44v5~+ cells and 11%Bcrp1~+ cells.
(2) Bcrp1~+ phenotype cells contain CK17~+ and CD44v5~+ cells,but the Bcrp1~- dose not.
(3) Bcrp1 and CK17 were expressed in one cell.
3 The analysis on the biological characteristics of Bcrp1~+ phenotype cells.
We use several different ways to analysis the biological characters of Bcrp1~+ phenotype Hela cells,and we get a conclusion that Bcrp1~+phenotype cells have the characters of cancer stem cells.
(1) After the observation of ultrastructures with electron microscope,we find that the Bcrp1~+ cells are large in size of nuclear and nucleoli are clearly.And there are rich of cytomicrosome and rough endoplasmic reticulum.But Bcrp1~- cells are large in size of nuclear and nucleoli are irregular type.The cytomicrosome are swell and cavitation a little,and the lipid droplet are increased in cytoplasm.
(2) We use flow Cytometry to identify the cycle of two group cells,and the result:almost all the Bcrp1~+cells are stay in the stage of G_0/G_1 and stage S,few of them are in the phase of mitosis;but there are more Bcrplcells in the phase of mitosis than Bcrp1~+cells;and SPF and PI of Bcrp1~+cells are larger than Bcrp1~-cells.The result of apoptosis rate with Annexin V show that only 0.2%Bcrp1~+cells are apoptosis,lower than Bcrplcells.
(3) When culture the two group cells we find that Bcrp1~+ cells have more vigor,80%Bcrp1~+cells can adhere very well 24h after sorting,but only 20% Bcrp1~-cells can adhere well 48h after sorting.
(4) Tumor cell migration and invasion assay by Boyden chamber Our results showed that Bcrp1~+cells have more migration and invasion ability through Matrigel than Bcrp1~-cells.At the end of the five hours,the number of invasive cells under the chamber showed that Bcrp1~+cells have more powerful migration ability than Bcrp1~-cells.This indicated Bcrp1~+cells could promote tumor cell migration and invasion in Matrigel by its direct degradation of Matrigel.
(5) We study on the expression of DNA-pk,PCNA and caspase-3 using western-blot,we find THAT the expression of DNA-pk and PCNA of Bcrp1~+cells are higher than Bcrp1~-cells,and the expression of caspase-3 of Bcrp1~+cells are lower.It indicated Bcrp1~+cells have more ability of DNA repairing and proliferating,more ability to against apoptosis.
(6) We use X-ray irradiate two group cells.91.7%Bcrp1~+cells will die when they irradiated by 15Gy;but almost all Bcrplcells will die with 12Gy.So we think Bcrp1~+cells have more ability to against irradiation.
[conclusion]
1 CK17,CD44v5,P63 and Bcrp1 are expressed in reserve cells of normal cervical tissue,and the expression are increased in cervical cancer.It seems that CK17 is stained in the margin of the cancer nest and the tumor embolus.In specimens with high grade malignant cancer or after the chemotherapy,the expression of CK17 and Bcrpl are increased.Double immunohistochemical examination show us that almost all cells which express CK17 are also express Bcrp1.CK17 and Bcrp1 are maybe the markers of cervical cancer stem cells.
2 Hela cells contained 0.7%CK17~+ cells,0.1%CD44v5~+ cells and 11%Bcrp1~+ cells.Bcrp1~+ phenotype cells contain CK17~+ and CD44v5~+ cells,but the Bcrp1~- dose not.Bcrp1 and CK17 were expressed in one cell.
3.Bcrp1~+cells have more vigor,they have more ability of proliferation,more ability of migration and invasion,more ability to against apoptosis,more ability to against irradiation,and more ability of DNA repairing.
4 Bcrp1~+phenotype cells have the characters of cancer stem cells.Even this phenotype is in low rate of Hela cells,but this group is very important for Hela cell line to keep immortalization.Bcrpl is maybe the markers of cervical cancer stem cells.This finding will help us to do more research about targeted therapy of cervical cancer.
本研究结合目前肿瘤干细胞的研究成果,对可能成为宫颈癌干细胞的标记物进行筛选,率先对Hela细胞中的Bcrpl~+亚群细胞进行了功能鉴定,由此推测Bcrpl~+可能成为宫颈癌干细胞标记物,丰富了实体肿瘤干细胞的研究,并为宫颈癌耐药机制的研究及多靶点药物治疗提供了全新的理论线索和支持。
[Object]One view of cancer is that it may arise from a single cell that has the ability to self-renew and thus to maintain the growth of a tumor,whereas the majority of its cellular progeny does not.A considerable effort is going into determining unique properties of these cells,because such cells might be expected to share properties with adult stem cells in normal tissues,they are often termed cancer stem cells.There is increasing evidence that cancers might contain their own stem cells.Many cancers, like normal organs,seem to be maintained by a hierarchical organization that includes slowly dividing stem cells,rapidly dividing transit amplifying cells(precursor cells), and differentiated cells.The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology.The presence of a small subpopulation of slowly dividing cancer stem cells might explain why so many cancers recur after treatment with irradiation or cytotoxic drugs,even when most of the cancer cells seem to be killed by the therapy.Usually,some cancer cells survive the treatment,and these surviving cells may be cancer stem cells,which may be not only resistant to the therapy but also essential for the malignancy of the cancer.However,in spite of old and more recent evidence that cancer stem cells exist,there is still a dearth of good phenotypic markers for such cells.In addition,many of the self-renewing cancer cell populations that are studied may also contain early progenitor cells that are derived from cancer stem cells but are also able to initiate and maintain tumor growth.Therefore,we join others to do some research about phenotypic markers for cervical caner stem cells.
Cervical cancer is a disease that results in devastating mortality,especially in developing countries,and it is the leading cause of cancer mortality and the second most common type of cancer in women worldwide after breast cancer.With the development of CSC theory,more and more gynecologists do a lot of research about cervical cancer stem cells,but non of them succeed.Because cervical cancer cells is difficult to be isolated from cervical tissues and there is also lack of classical markers of cervical stem cells.So it is the key point to find the cervical cancer stem cells.According to the researches about the CSC and cervical reserve cells,we choose CK17,CD44v5,P63,Bcrp1 as markers and investigate the expression of CK17, CD44v5,P63,Bcrp1 in cervical cancer tissue and HeLa cell line.We also identify the Characterization of Bcrp 1~+ HeLa cells.
[Methods and results]
1 The expression of CK17,CD44v5,P63 and Bcrp1 in normal cervical tissue and cervical squamous cancer specimens.
We investigated a total 75 specimens:cervical squamous cancer(n=55),normal cervix(n=20).All cases were analysed immunohistochemically using antibodies against CK17,CD44v5,P63 and Bcrp1.The results as follow:
(1) CK17 is expressed in reserve cells cytoplasm in normal cervical specimens.The expression were increased in cervical squamous cancer specimens. And with the metastatic,the expression of CK17 is increased and it seems that CK17 is stained in the margin of the cancer nest and the tumor embolus.In specimens with high grade malignant cancer or after the chemotherapy,the expression of CK17 is increased.
(2) p63 is stained in nuclei of reserve cells and almost all cancer cells.
(3) CD44v5 is stained in reserve cells and a part of cancer cells membranes.The expression is increased in cervical squamous cancer specimens.But the expression of CD44v5 is irregularly and the it is not increased as much as others markers.
(4) Bcrp1 is stained in reserve cells and a part of cancer cells membranes.In specimens with high grade malignant cancer or after chemotherapy,the expression of Bcrp1 is increased too.
(5) The result of double immunohistochemical examination show us that almost all cells which express CK17 are also express Bcrpl,but not all cells which express Bcrpl are express CK17.
2 The isolation of CK17~+,CD44v5~+and Bcrp1~+ cell in Hela cell line
We use flow Cytometry to identify and isolate the CK17~+,CD44v5~+ and Bcrp1~+ cells in Hela cell line.Result:
(1) Hela cells contained 0.7%CK17~+ cells,0,1%CD44v5~+ cells and 11%Bcrp1~+ cells.
(2) Bcrp1~+ phenotype cells contain CK17~+ and CD44v5~+ cells,but the Bcrp1~- dose not.
(3) Bcrp1 and CK17 were expressed in one cell.
3 The analysis on the biological characteristics of Bcrp1~+ phenotype cells.
We use several different ways to analysis the biological characters of Bcrp1~+ phenotype Hela cells,and we get a conclusion that Bcrp1~+phenotype cells have the characters of cancer stem cells.
(1) After the observation of ultrastructures with electron microscope,we find that the Bcrp1~+ cells are large in size of nuclear and nucleoli are clearly.And there are rich of cytomicrosome and rough endoplasmic reticulum.But Bcrp1~- cells are large in size of nuclear and nucleoli are irregular type.The cytomicrosome are swell and cavitation a little,and the lipid droplet are increased in cytoplasm.
(2) We use flow Cytometry to identify the cycle of two group cells,and the result:almost all the Bcrp1~+cells are stay in the stage of G_0/G_1 and stage S,few of them are in the phase of mitosis;but there are more Bcrplcells in the phase of mitosis than Bcrp1~+cells;and SPF and PI of Bcrp1~+cells are larger than Bcrp1~-cells.The result of apoptosis rate with Annexin V show that only 0.2%Bcrp1~+cells are apoptosis,lower than Bcrplcells.
(3) When culture the two group cells we find that Bcrp1~+ cells have more vigor,80%Bcrp1~+cells can adhere very well 24h after sorting,but only 20% Bcrp1~-cells can adhere well 48h after sorting.
(4) Tumor cell migration and invasion assay by Boyden chamber Our results showed that Bcrp1~+cells have more migration and invasion ability through Matrigel than Bcrp1~-cells.At the end of the five hours,the number of invasive cells under the chamber showed that Bcrp1~+cells have more powerful migration ability than Bcrp1~-cells.This indicated Bcrp1~+cells could promote tumor cell migration and invasion in Matrigel by its direct degradation of Matrigel.
(5) We study on the expression of DNA-pk,PCNA and caspase-3 using western-blot,we find THAT the expression of DNA-pk and PCNA of Bcrp1~+cells are higher than Bcrp1~-cells,and the expression of caspase-3 of Bcrp1~+cells are lower.It indicated Bcrp1~+cells have more ability of DNA repairing and proliferating,more ability to against apoptosis.
(6) We use X-ray irradiate two group cells.91.7%Bcrp1~+cells will die when they irradiated by 15Gy;but almost all Bcrplcells will die with 12Gy.So we think Bcrp1~+cells have more ability to against irradiation.
[conclusion]
1 CK17,CD44v5,P63 and Bcrp1 are expressed in reserve cells of normal cervical tissue,and the expression are increased in cervical cancer.It seems that CK17 is stained in the margin of the cancer nest and the tumor embolus.In specimens with high grade malignant cancer or after the chemotherapy,the expression of CK17 and Bcrpl are increased.Double immunohistochemical examination show us that almost all cells which express CK17 are also express Bcrp1.CK17 and Bcrp1 are maybe the markers of cervical cancer stem cells.
2 Hela cells contained 0.7%CK17~+ cells,0.1%CD44v5~+ cells and 11%Bcrp1~+ cells.Bcrp1~+ phenotype cells contain CK17~+ and CD44v5~+ cells,but the Bcrp1~- dose not.Bcrp1 and CK17 were expressed in one cell.
3.Bcrp1~+cells have more vigor,they have more ability of proliferation,more ability of migration and invasion,more ability to against apoptosis,more ability to against irradiation,and more ability of DNA repairing.
4 Bcrp1~+phenotype cells have the characters of cancer stem cells.Even this phenotype is in low rate of Hela cells,but this group is very important for Hela cell line to keep immortalization.Bcrpl is maybe the markers of cervical cancer stem cells.This finding will help us to do more research about targeted therapy of cervical cancer.
引文
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