低剂量辐射生物效应机制初探
摘要
低剂量电离辐射具有兴奋效应及适应性效应。1984年Olivier等首次观察到人淋巴细胞经LDR后对随后的大剂量辐射染色体突变减少,提出了LDR的适应性效应。国内外学者进行了大量研究证明低剂量全身或仅是脾区辐射可刺激动物的生长、发育,可延长动物寿命,提高生育力,同时还发现可增强动物和人体的免疫功能,降低肿瘤发生率以及能对肿瘤治疗起到协同等现象。
肝癌是我国常见、高发的恶性肿瘤,预后差。目前治疗主要以手术治疗为主,但由于肿瘤病灶的位置、周围血管及淋巴管等限制,导致手术治疗受到很大限制。同时由于肝癌细胞对于化疗药物的敏感性差,故目前部分肝癌治疗以放射治疗为主。但由于正常肝组织对于放射治疗的耐受剂量小于肝癌细胞的放射剂量,导致放射治疗明显受到限制。因此,如何进一步提高放射治疗效果,如何提高肝癌放射治疗的效率,是摆在肿瘤研究工作者面前的一个亟待解决的问题。
PI3K/Akt信号转导途径参与调节细胞存活信号通路、基因表达调控、细胞代谢和细胞骨架重建等生理功能,诱导细胞增殖、分化,避免细胞发生凋亡。研究表明,电离辐射、紫外线和细胞毒性药物均可能激活PI3K/Akt信号转导途径,导致肿瘤细胞进行应激调节,维持细胞生命活动的稳定。
本文主要研究低剂量照射(LDR)对人正常细胞(HL7702细胞、293T细胞、6550HLEpiC细胞)及肿瘤细胞(BEL7402细胞、HCT-8细胞、Hela细胞)增殖、细胞周期及相关信号蛋白表达的影响。LDR后上述正常细胞增殖加速,而对上述肿瘤细胞无此效应。同时HL7702细胞经75 mGy LDR后再给予2 Gy辐射可诱导出适应性反应,而BEL7402细胞75 mGy LDR后再给予2Gy辐射其凋亡较单纯2 Gy照射增多。应用Protein Array系统检测细胞增殖及凋亡相关蛋白的表达情况。并进一步对PDK1、CyclinD1、p27、Akt及Rb蛋白进行检测,提示PDK1、Akt、p27、CyclinD1及Rb参与了相关的信号转导。本课题为寻找新的有效提高放射治疗增益的治疗靶点,增加肝癌细胞的辐射敏感性,克服辐射耐受性,提高肝癌的放射治疗效果提供有益的线索和理论基础。同时为辐射防护提供理论依据。
The difference between low dose radiation and high dose radiation has been proven by many experiments. High dose radiation is harmful for humanbeing.However; low dose radiation can produce the adaptive effect and improve the immunity. The mechanism of the low dose radiation has not been clear. DNA repair may be related to the adaptive effect.P53 play an important role in the adaptive effect. The protein synthesis and metabolism all take part in the low dose radiation effect.
Hepatocellular carcinoma is frequent occurrence in our country. The main treatment is operation. But limited to the local site of tumor and adjuvant vessels, operation is limited. At the same time, the carcinoma is not sensitive to the chemotherapy. The radiotherapy has played a role in the treatment. But the tumor cell radiation dose is larger than the normal cell endurance dose. So the radiotherapy is limited. How to improve the radiotherapy effect and reduce the harm effect is questional.The low dose combined with the high dose radiation can increase the apoptosis of tumor cell.
The research is mainly focus on the BEL7402 cell line and HL7702 cell line effect after low dose radiation. Further explore the mechanism of the different effect; mainly included the PDK1 and the following protein, such as p27, Akt and Rb.Our project can make some theory base to the focus site of radiotherapy.
Part 1 the different effect of normal cell and tumor cell and the mechism
1. The effect on proliferation and cell cycle of LDR on normal cell and tumor cell
25 mGy、50 mGy、75 mGy、100 mGy、200 mGy low dose radiation and 1 Gy high dose radiation on HL7702,6550HLEpiC,293T and BEL7402,HCT-8 and Hela cell line. After radiation, different time cell count, MTT experiment and flowcytometry to explore the cell cycle. The results showed that the low dose radiation can stimulate the proliferation of normal cell line. But the tumor cell proliferation was not changed. The LDR had no effect on the cell cycle of normal cell and tumor cell line.
2. The mechanism of LDR on tumor cell and normal cell
In order to explore the different effect mechanism, we used the protein array to find protein changes related to cell cycle. Many protein expressions has been changed after LDR.Our experiment has found that phospharylated Rb protein expression has been increase after LDR in human bone marrow mechymal stem cell. The Rb protein play an important role in G1 to S swith.The phospharylated Rb protein free the E2F factor and take part in cell cycle regulation. Our experiment observed that the phosphorylated Rb protein decreased in BEL7402 and increased in HL7702 cell line.
2.1 The phospharylated Rb protein expression in HL7702 cell line and BEL7402 cell line. The phospharylated Rb protein expression was increased in HL7702 cell line after LDR.In BEL7402 cell line the phospharylated Rb protein expression decreased after LDR.
2.2 The cyclinD1 expression in HL7702 cell line and BEL7402 cell line The expression of cyclinD1 increased in HL7702 cell line after LDR, and decreased in BEL7402 cell line after LDR.
2.3 The expression of phospharylated PDK1 in HL7702 cell line and BEL7402 cell line. The phospharylaed PDK1 expression increased in HL7702 cell line after LDR, and decreased in BEL7402 cell line after LDR.
2.4 The expression of phospharylate Akt in HL7702 and BEL7402 cell line. The expression of phospharylaed of Akt expression increased in HL7702 cell line and decreased in BEL7402 cell line after LDR.
Part2 the adaptive effect of LDR and mechanism
1. The effect on normal cell and tumor cell proliferation of LDR combined with high dose radiation
HL7702 cell line and BEL7402 cell line were irradiated by low dose radiation and combined with high dose radiation. The cell count and flowcytometry carried on after the radiation. There was adaptive effect on HL7702 cell line but no adaptive in EBL7402 cell line. The apoptosis increased in BEL7402 cell line after low dose radiation combined with high dose radiation.
2. The mechanism of LDR combined with high dose radiation in HL7702 and BEL7402 cell line.
The protein related to cell cycle has been explored by protein array. Some protein expression increased and some decreased.PI3K/Akt cell signaling pathway mainly regulate the cell apoptosis, proliferation and differentiation. So we explore the expression of Akt and related protein expression.
2.1 The expression of p27 in HL7702 and BEL7402 cell line after LDR combined with high dose radiation. The expression of p27 increased in HL7702 and BEL7402 cell line. The expression was more in the combined group in BEL7402 cell line. But less in the combined group in HL7702 cell line.
2.2 The expression of phospharylated Rb in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-Rb decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
2.3 The expression of phospharylated Akt in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-Akt increased in HL7702 and BEL7402 cell line. The expression was less in the combined group in HL7702 cell line. But more in the combined group in BEL7402 cell line.
2.4 The expression of phospharylated PDK1 in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-PDK1 decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
2.5 The expression of cyclinD1 in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-PDK1 decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
In one word, LDR can produce the stimulating and adaptive effect on normal cell but not in tumor cell. The protein of PDK1, Rb may be related to the effect.
肝癌是我国常见、高发的恶性肿瘤,预后差。目前治疗主要以手术治疗为主,但由于肿瘤病灶的位置、周围血管及淋巴管等限制,导致手术治疗受到很大限制。同时由于肝癌细胞对于化疗药物的敏感性差,故目前部分肝癌治疗以放射治疗为主。但由于正常肝组织对于放射治疗的耐受剂量小于肝癌细胞的放射剂量,导致放射治疗明显受到限制。因此,如何进一步提高放射治疗效果,如何提高肝癌放射治疗的效率,是摆在肿瘤研究工作者面前的一个亟待解决的问题。
PI3K/Akt信号转导途径参与调节细胞存活信号通路、基因表达调控、细胞代谢和细胞骨架重建等生理功能,诱导细胞增殖、分化,避免细胞发生凋亡。研究表明,电离辐射、紫外线和细胞毒性药物均可能激活PI3K/Akt信号转导途径,导致肿瘤细胞进行应激调节,维持细胞生命活动的稳定。
本文主要研究低剂量照射(LDR)对人正常细胞(HL7702细胞、293T细胞、6550HLEpiC细胞)及肿瘤细胞(BEL7402细胞、HCT-8细胞、Hela细胞)增殖、细胞周期及相关信号蛋白表达的影响。LDR后上述正常细胞增殖加速,而对上述肿瘤细胞无此效应。同时HL7702细胞经75 mGy LDR后再给予2 Gy辐射可诱导出适应性反应,而BEL7402细胞75 mGy LDR后再给予2Gy辐射其凋亡较单纯2 Gy照射增多。应用Protein Array系统检测细胞增殖及凋亡相关蛋白的表达情况。并进一步对PDK1、CyclinD1、p27、Akt及Rb蛋白进行检测,提示PDK1、Akt、p27、CyclinD1及Rb参与了相关的信号转导。本课题为寻找新的有效提高放射治疗增益的治疗靶点,增加肝癌细胞的辐射敏感性,克服辐射耐受性,提高肝癌的放射治疗效果提供有益的线索和理论基础。同时为辐射防护提供理论依据。
The difference between low dose radiation and high dose radiation has been proven by many experiments. High dose radiation is harmful for humanbeing.However; low dose radiation can produce the adaptive effect and improve the immunity. The mechanism of the low dose radiation has not been clear. DNA repair may be related to the adaptive effect.P53 play an important role in the adaptive effect. The protein synthesis and metabolism all take part in the low dose radiation effect.
Hepatocellular carcinoma is frequent occurrence in our country. The main treatment is operation. But limited to the local site of tumor and adjuvant vessels, operation is limited. At the same time, the carcinoma is not sensitive to the chemotherapy. The radiotherapy has played a role in the treatment. But the tumor cell radiation dose is larger than the normal cell endurance dose. So the radiotherapy is limited. How to improve the radiotherapy effect and reduce the harm effect is questional.The low dose combined with the high dose radiation can increase the apoptosis of tumor cell.
The research is mainly focus on the BEL7402 cell line and HL7702 cell line effect after low dose radiation. Further explore the mechanism of the different effect; mainly included the PDK1 and the following protein, such as p27, Akt and Rb.Our project can make some theory base to the focus site of radiotherapy.
Part 1 the different effect of normal cell and tumor cell and the mechism
1. The effect on proliferation and cell cycle of LDR on normal cell and tumor cell
25 mGy、50 mGy、75 mGy、100 mGy、200 mGy low dose radiation and 1 Gy high dose radiation on HL7702,6550HLEpiC,293T and BEL7402,HCT-8 and Hela cell line. After radiation, different time cell count, MTT experiment and flowcytometry to explore the cell cycle. The results showed that the low dose radiation can stimulate the proliferation of normal cell line. But the tumor cell proliferation was not changed. The LDR had no effect on the cell cycle of normal cell and tumor cell line.
2. The mechanism of LDR on tumor cell and normal cell
In order to explore the different effect mechanism, we used the protein array to find protein changes related to cell cycle. Many protein expressions has been changed after LDR.Our experiment has found that phospharylated Rb protein expression has been increase after LDR in human bone marrow mechymal stem cell. The Rb protein play an important role in G1 to S swith.The phospharylated Rb protein free the E2F factor and take part in cell cycle regulation. Our experiment observed that the phosphorylated Rb protein decreased in BEL7402 and increased in HL7702 cell line.
2.1 The phospharylated Rb protein expression in HL7702 cell line and BEL7402 cell line. The phospharylated Rb protein expression was increased in HL7702 cell line after LDR.In BEL7402 cell line the phospharylated Rb protein expression decreased after LDR.
2.2 The cyclinD1 expression in HL7702 cell line and BEL7402 cell line The expression of cyclinD1 increased in HL7702 cell line after LDR, and decreased in BEL7402 cell line after LDR.
2.3 The expression of phospharylated PDK1 in HL7702 cell line and BEL7402 cell line. The phospharylaed PDK1 expression increased in HL7702 cell line after LDR, and decreased in BEL7402 cell line after LDR.
2.4 The expression of phospharylate Akt in HL7702 and BEL7402 cell line. The expression of phospharylaed of Akt expression increased in HL7702 cell line and decreased in BEL7402 cell line after LDR.
Part2 the adaptive effect of LDR and mechanism
1. The effect on normal cell and tumor cell proliferation of LDR combined with high dose radiation
HL7702 cell line and BEL7402 cell line were irradiated by low dose radiation and combined with high dose radiation. The cell count and flowcytometry carried on after the radiation. There was adaptive effect on HL7702 cell line but no adaptive in EBL7402 cell line. The apoptosis increased in BEL7402 cell line after low dose radiation combined with high dose radiation.
2. The mechanism of LDR combined with high dose radiation in HL7702 and BEL7402 cell line.
The protein related to cell cycle has been explored by protein array. Some protein expression increased and some decreased.PI3K/Akt cell signaling pathway mainly regulate the cell apoptosis, proliferation and differentiation. So we explore the expression of Akt and related protein expression.
2.1 The expression of p27 in HL7702 and BEL7402 cell line after LDR combined with high dose radiation. The expression of p27 increased in HL7702 and BEL7402 cell line. The expression was more in the combined group in BEL7402 cell line. But less in the combined group in HL7702 cell line.
2.2 The expression of phospharylated Rb in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-Rb decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
2.3 The expression of phospharylated Akt in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-Akt increased in HL7702 and BEL7402 cell line. The expression was less in the combined group in HL7702 cell line. But more in the combined group in BEL7402 cell line.
2.4 The expression of phospharylated PDK1 in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-PDK1 decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
2.5 The expression of cyclinD1 in HL7702 cell line and BEL7402 cell line after LDR combined with high dose radiation
The expression of p-PDK1 decreased in HL7702 and BEL7402 cell line. The expression was less in the combined group in BEL7402 cell line. But more in the combined group in HL7702 cell line.
In one word, LDR can produce the stimulating and adaptive effect on normal cell but not in tumor cell. The protein of PDK1, Rb may be related to the effect.
引文
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