脂肪酸及其代谢产物和相关基因在癌症代谢中的作用
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摘要
参与癌症的特定分子的识别和阻止这些分子的抑制剂的开发,作为靶治疗,是目前癌症研究的一个令人兴奋和感兴趣的领域。在很多疾病(包括癌症)中都发现了多不饱和脂肪酸(polyunsaturated fatty acids, PUFAs)[例如：花生四烯酸arachidonic acid, AA, C20:4(6)]及其代谢产物(例如：Prostagland E2, PGE2)的重要作用。然而,它们是如何参与癌细胞代谢,在此代谢中起到什么样的作用仍不清楚。本研究以癌细胞(MDA-MB-231细胞、MCF-7细胞、ZR-75-1细胞、]HT-29细胞和B16细胞)、人乳腺癌样本(正常组织、癌旁组织和乳腺癌组织)和转△6去饱和酶(delta-6 desaturase, D6D)基因的黑色素瘤小鼠模型为研究对象,在分子水平、细胞水平和动物载体实验,通过观察AA、AA代谢产物PGE2、与AA合成相关的去饱和酶(D6D)和与癌症的发生和发展相关的一系列基因的改变,来探讨D6D与癌症的发生是否有相关性。为进一步的体内和临床研究奠定基础。主要研究方法和结果如下：
一、抗癌药物对癌细胞内长链脂肪酸及其代谢产物和相关基因的影响
方法：采用XTT方法检测癌细胞增殖；气相色谱(Gas chromatography, GC)分析脂肪酸含量；实时定量PCR (real time PCR)检测硬脂酰-CoA去饱和酶-1(stearoyl-CoAdesaturase-1, SCD1)、Δ5去饱和酶(delta-5-desaturase, D5D)、D6D、环氧酶Ⅱ(cyclooxygenaseⅡ, COX-2) mRNA表达水平；Western Blotting检测D5D和D6D蛋白表达水平；酶联免疫吸附法(ELISA)测定PGE2浓度。
结果：
1.随CPT浓度从0.0625～2μmol／L增大,对癌细胞的抑制率增加(P<0.05或P<0.01)；随Ber浓度从4-64μg／ml增大,对癌细胞的抑制率增加(P<0.05或P<0.01)。
2. Ber(终浓度8μg／ml或者16μg／ml)和CPT(终浓度0.25μmol／L或者0.5μmol／L)分别处理5株癌细胞,各癌细胞株内PUFAs占总脂肪酸的百分比发生了变化,但共同特点是：所有癌细胞株内的AA发生的变化最明显(P<0.05)。
3.和对照组比较,Ber和CPT处理组,所有癌细胞株的D5D和D6D mRNA表达水平都显著性提高(P<0.05或者P<0.01)；HT-19细胞的CPT处理组,SCD1mRNA表达水平非常显著性提高(P<0.01)；B16细胞的CPT处理组,SCD1 mRNA表达水平显著性降低(P<0.05)；其余细胞株的Ber或者CPT处理组,SCD1 mRNA表达水平变化不明显；MDA-MB-231细胞、MCF-7细胞和ZR-75-1细胞的Ber和CPT处理组,COX-2 mRNA表达水平都显著性提高(P<0.05或者P<0.01)；HT-29细胞和B16细胞,COX-2 mRNA表达水平都显著性降低(P<0.05或者P<0.01)。
4.5株癌细胞的Ber和CPT处理组和对照组比较,D5D和D6D蛋白质表达水平明显提高。
5.和对照组比较,除了B16细胞的Ber和CPT处理组,PGE2产量减少外,其余4株癌细胞的Ber和CPT处理组,PGE2产量全部被提高。
结论：D5D和D6D表达水平的提高导致了AA的增加,同时PGE2的产量也明显增加；D5D和D6D表达水平的降低导致了AA的减少,同时PGE2的产量也明显减少。这暗示了D5D和D6D可以作为发现和治疗癌症的生物学靶点。
二、人乳腺癌组织中D6D的变化
方法：GC分析脂肪酸含量；D6D的活性检测通过测量LA/AA的比率；realtime PCR检测D6D mRNA表达水平；Western Blotting检测D6D蛋白表达水平；ELISA测定PGE2浓度。
结果：
1.与正常组织和癌旁组织比较,在癌症组织中LA和ALA的转换显著性增加,说明D6D的活性显著性增高。
2.与正常组织和癌旁组织比较,在癌症组织中D6D mRNA表达分别增高64和50倍；通过Western blot检测也发现,癌症组织和临近组织内D6D蛋白质表达比正常组织有显著性增高；正常组织和癌旁组织之间比较,D6D mRNA表达和蛋白质没有发生显著性变化。
3.在癌症组织中PGE2含量比正常组织和癌旁组织中PGE2含量显著性增高。正常组织和癌旁组织比较,PGE2含量无明显变化。
结论：D6D活性和表达水平的增高导致了AA的增加,同时PGE2的产量也明显增加,暗示D6D可以作为治疗癌症的生物学靶点。
三、体外和体内肿瘤生成过程中D6D的作用
方法：B16细胞用表皮生长因子(epidermal growth factor, EGF)、成纤维细胞生长因子(fibroblast growth factor, FGF)、反应氧化种类(例如H2O2)、辐射(例如UV光和X-射线)、酸性条件(pH 6.5)和缺氧条件处理。处理后的细胞用GC来分析脂肪酸含量,real time PCR检测D6D和PPARa mRNA表达和Western blotting检测D6D蛋白质表达；将D6D基因转入B16黑色素瘤细胞使D6D基因过表达,通过RNAi技术来降低D6D基因表达；细胞生长曲线和迁移实验评测体外肿瘤生成过程中D6D的作用；分别注射D6D过表达(D6D-over)和空载体(Vector-control)的B16细胞进入C57BL/6小鼠体内,肿瘤生长情况每天用卡尺通过测量肿瘤的长和宽来监控,按照以下公式计算肿瘤体积：volume=(1/2)Lw2,评定肿瘤形成的影响和肿瘤生长率；PCR array分析癌症相关基因。
结果：
1.所用到的生长因子和死亡挑战因子都显著性加强LA向AA的转换,增加了D6D的活性。
2. D6D mRNA表达被生长因子和死亡挑战因子上调,D6D蛋白水平除了在酸性条件(pH 6.5)下没有被提高外,在上面提到的所有因子的作用下都被上调。
3.在B16细胞内PPAR-a被生长和死亡挑战因子显著性提高,个别因子对PPAR-a mRNA表达的调节与相应的D6D表达不成比例。
4.在体外过表达D6D促进B16细胞增长,而敲除D6D则抑制B16细胞增长；在体外过表达D6D促进B16细胞迁移,而敲除D6D则抑制B16细胞迁移。
6.在体内过表达D6D促进B16黑色素瘤生长。
7.与Vector-control组比较,在D6D-over B16组黑色素瘤中AA和PGE2含量较高。
8.肿瘤生成时,抗凋亡基因(bax、bcl-2、bcl-2l1和survivin)、原癌基因(brcal、fos、jun、met和myc)、转录因子(nfkbl和nfkbia)和血管形成相关基因(pdgfa、pdgfb、vegfa、vegfb和vegfc)被上调,而癌症抑制基因pten被下调约64倍。
结论：证明了AA、D6D和PGE2与癌症发生密切相关,D6D可以作为一个新的抗癌靶点。
总之,本研究发现多不饱和脂肪酸参与了肿瘤的发生,D6D的活性和表达量的提高可以促进癌症的发生和迁移,提示D6D可以作为一个新的抗癌靶点。
Identification of specific molecules involved in cancer and the development of inhibitors to block these molecules-targeted therapies-is an exciting and interesting area of current cancer research. polyunsaturated fatty acids (PUFAs) (such as, arachidonic acid, AA) and their metabolites (such as, prostaglandin E2, PGE2) were found in many disease, including cancer. However, how they participate in the cancer cells metabolism and What kind of role play in the metabolism is still not clear. In this study, cancer cell, breast cancer sample and transfer delta-6 dehydrogenase genes in mice model as research object, at the molecular level, cell and animal level, through observing the change of AA, AA metabolites PGE2 and AA synthesis of related desatuarase (D6D) and a series of gene related to the occurrence and the development of cancer, to explore whether D6D correlated with cancerogenesis. This will lay the foundation for further clinical studies in vivo and clinic study. Main research methods and the results are as follows:
1. Effect of anti-cancer drug on PUFAs, their metabolites and related gene in cancer cells
Methods:The proliferation of cells was detected by XTT, and the profile of fatty acids was examined by Gas chromatography (GC). In addition, stearoyl-CoA desaturase-1 (SCD1), delta-5-desaturase (D5D), D6D and cyclooxygenase II (COX-2) mRNA expression were measured by the real-time reverse transcription. D5D and D6D protein expression were measured by Western Blotting.The PGE2 production was determined by enzyme-linked immunosorbent assay.
Results:
a. After being treated with CPT (0.0625-2μM), the Inhibiton ratio of cancer cells gradually increased (P<0.05 or P<0.01); After being treated with Ber (0.0625-2μM), the Inhibiton ratio of cancer cells gradually increased (P<0.05 or P<0.01).
b. After being treated with Ber (8μg/ml or16μg/ml) and CPT (0.25μMor0.5μM), respectively, the percent of PUFAs in these five cancer cell lines change, but the common characteristics is:the chang of AA is significant in all cancer cell lines (P<0.05).
c. Compared to control group, the expression of D5D and D6D mRNA were significantly increased in Ber and CPT treated group (P<0.05 or P<0.01); CPT treated in HT-29 cell group, the expression of SCD1 mRNA were significantly increased (P<0.01); CPT treated in B16 cell group, the expression of SCD1 mRNA were significantly decreased (P<0.05); Ber or CPT treated in other cell groups, the expression of SCD1 mRNA were not changed; Ber and CPT treated in MDA-MB-231, MCF-7 and ZR-75-1 cell group, the expression of COX-2 mRNA were significantly increased (P<0.01); Ber and CPT treated in HT-29 and B16 cell group, the expression of SCD1 mRNA were significantly decreased (P<0.05 or P<0.01).
d. Ber or CPT treated in all cell groups, the expression of D5D and D6D protein were obversely increased.
e. Ber or CPT treated in other four cell groups, the product of PGE2 were raised except for B16 cell.
Conclusions:the improvement of expression of D5D and D6D induced the increase of AA, and the product of PGE2 were obversely raised; the reduce of expression of D5D and D6D induced the decrease of AA, and the product of PGE2 were obversely reduced. This suggests D5D and D6D can be as the biological targets of the found and treatment of cancer biology.
2. Change of D6D in human Breast cancertissue
Methods:the profile of fatty acids was examined by GC. the activity of D6D was measured by the ratio of LA/AA. D6D mRNA expression were measured by the real-time reverse transcription. D5D and D6D protein expression were measured by Western Blotting. The PGE2 production was determined by enzyme-linked immunosorbent assay.
Results:
a. The conversion of LA and ALA, as indicated by the ratio of LA/AA and ALA/EPA, were significantly enhanced in tumor tissues comparing to normal and adjacent tissues, suggest the acivity of D6D was significantly improved.
b. Expression of D6D mRNA was up-regulated by 64 folds and 50 folds in human breast cancer comparing to normal and adjacent tissues; Expression of D6D protein was up-regulated in human breast cancer comparing to normal and adjacent tissues; Expression of D6D mRNA and protein were changed in normal tissues comparing to adjacent tissues.
c. The product of PGE2 was significantly raised in human breast cancer comparing to normal and adjacent tissues; The product of PGE2 was changed in normal tissues comparing to adjacent tissues.
Conclusions:State the up-regulation of activity and expression of D6D induced the increase of AA, at the same time, the product of PGE2 was also obversely improved, suggest D6D can be as the biology target of treating cancer.
3. Role of D6D in vitro and in melanoma growth in vivo
Methods:B16 cell treated with growth factors, including epidermal growth factor (EGF), fibroblast growth factor (FGF), et al, Oxidation reaction type (H2O2), radiation (UV light and X-array), Acidic conditions (pH 6.5) and hypoxia conditions. After B16 cell was treated by these factors, the profile of fatty acids was examined by GC, the activity of D6D was measured by the ratio of LA/AA, D6D and PPARa mRNA expression were measured by the real-time reverse transcription, D6D protein expression were measured by Western Blotting. Inoculate Cancer cells into mouse, tumor growth will be monitored everyday by measuring the length (L) and width (w) of the tumor with a caliper and calculating tumor volume on the basis of the following formula:volume= (1/2)Lw2, to assess he incidence of tumor formation and tumor growth rate. cancer-related genes were analysed by PCR array. The PGE2 production was determined by ELISA,
Results:
a. The activity of D6D is significantly higher in growth and death-challenging factors than in control, and the activity of D6D is increased.
b. The expression of D6D mRNA was up-regulated by growth and death-challenging factors, The expression of D6D protein was up-regulated by growth and death-challenging factors except for Acidic conditions (pH 6.5).
c. PPAR-a was significantly up-regulated in B16 cells by both growth and death-challenging factors, However, the regulation of PPAR-a mRNA expression by individual factors was not proportional to the corresponding levels of D6D expression.
d. Over-expression of D6D promoted B16 cell growth while knock-down of D6D inhibited B16 cell growth in vitro.
e. Over-expression of D6D promoted B16 cell migration while knock-down of D6D inhibited B16 cell migration in vitro.
f. Over-expression of D6D promoted B16 melanoma growth in vivo.
g. AA and PGE2 was higher in D6D-over B16 melanoma than in Vector-control.
h. Expression of several genes that are involved in tumorigenesis, such as anti-apoptotic genes (bax, bcl-2, bcl-211 and survivin), oncogenes (brcal,fos,jun, met and myc), transcriptional factors (nfkbland nfkbia), and angiogenesis related genes (pdgfa, pdgfb, vegfa, vegfb and vegfc) were up-regulated, while the cancer-suppressor gene pten was down-regulated by 64 folds.
Conclusions:Testify AA, D6D and PGE2 Closely related with cancer, and D6D can be used as a new anti-cancer targets.
In summary, the study suggest PUFAs involve in the cancerogenesis and the up-regulation of the activity and expression of D6D can promote cancerogenesis and migration, then, D6D act as a new anti-cancer target.
一、抗癌药物对癌细胞内长链脂肪酸及其代谢产物和相关基因的影响
方法：采用XTT方法检测癌细胞增殖；气相色谱(Gas chromatography, GC)分析脂肪酸含量；实时定量PCR (real time PCR)检测硬脂酰-CoA去饱和酶-1(stearoyl-CoAdesaturase-1, SCD1)、Δ5去饱和酶(delta-5-desaturase, D5D)、D6D、环氧酶Ⅱ(cyclooxygenaseⅡ, COX-2) mRNA表达水平；Western Blotting检测D5D和D6D蛋白表达水平；酶联免疫吸附法(ELISA)测定PGE2浓度。
结果：
1.随CPT浓度从0.0625～2μmol／L增大,对癌细胞的抑制率增加(P<0.05或P<0.01)；随Ber浓度从4-64μg／ml增大,对癌细胞的抑制率增加(P<0.05或P<0.01)。
2. Ber(终浓度8μg／ml或者16μg／ml)和CPT(终浓度0.25μmol／L或者0.5μmol／L)分别处理5株癌细胞,各癌细胞株内PUFAs占总脂肪酸的百分比发生了变化,但共同特点是：所有癌细胞株内的AA发生的变化最明显(P<0.05)。
3.和对照组比较,Ber和CPT处理组,所有癌细胞株的D5D和D6D mRNA表达水平都显著性提高(P<0.05或者P<0.01)；HT-19细胞的CPT处理组,SCD1mRNA表达水平非常显著性提高(P<0.01)；B16细胞的CPT处理组,SCD1 mRNA表达水平显著性降低(P<0.05)；其余细胞株的Ber或者CPT处理组,SCD1 mRNA表达水平变化不明显；MDA-MB-231细胞、MCF-7细胞和ZR-75-1细胞的Ber和CPT处理组,COX-2 mRNA表达水平都显著性提高(P<0.05或者P<0.01)；HT-29细胞和B16细胞,COX-2 mRNA表达水平都显著性降低(P<0.05或者P<0.01)。
4.5株癌细胞的Ber和CPT处理组和对照组比较,D5D和D6D蛋白质表达水平明显提高。
5.和对照组比较,除了B16细胞的Ber和CPT处理组,PGE2产量减少外,其余4株癌细胞的Ber和CPT处理组,PGE2产量全部被提高。
结论：D5D和D6D表达水平的提高导致了AA的增加,同时PGE2的产量也明显增加；D5D和D6D表达水平的降低导致了AA的减少,同时PGE2的产量也明显减少。这暗示了D5D和D6D可以作为发现和治疗癌症的生物学靶点。
二、人乳腺癌组织中D6D的变化
方法：GC分析脂肪酸含量；D6D的活性检测通过测量LA/AA的比率；realtime PCR检测D6D mRNA表达水平；Western Blotting检测D6D蛋白表达水平；ELISA测定PGE2浓度。
结果：
1.与正常组织和癌旁组织比较,在癌症组织中LA和ALA的转换显著性增加,说明D6D的活性显著性增高。
2.与正常组织和癌旁组织比较,在癌症组织中D6D mRNA表达分别增高64和50倍；通过Western blot检测也发现,癌症组织和临近组织内D6D蛋白质表达比正常组织有显著性增高；正常组织和癌旁组织之间比较,D6D mRNA表达和蛋白质没有发生显著性变化。
3.在癌症组织中PGE2含量比正常组织和癌旁组织中PGE2含量显著性增高。正常组织和癌旁组织比较,PGE2含量无明显变化。
结论：D6D活性和表达水平的增高导致了AA的增加,同时PGE2的产量也明显增加,暗示D6D可以作为治疗癌症的生物学靶点。
三、体外和体内肿瘤生成过程中D6D的作用
方法：B16细胞用表皮生长因子(epidermal growth factor, EGF)、成纤维细胞生长因子(fibroblast growth factor, FGF)、反应氧化种类(例如H2O2)、辐射(例如UV光和X-射线)、酸性条件(pH 6.5)和缺氧条件处理。处理后的细胞用GC来分析脂肪酸含量,real time PCR检测D6D和PPARa mRNA表达和Western blotting检测D6D蛋白质表达；将D6D基因转入B16黑色素瘤细胞使D6D基因过表达,通过RNAi技术来降低D6D基因表达；细胞生长曲线和迁移实验评测体外肿瘤生成过程中D6D的作用；分别注射D6D过表达(D6D-over)和空载体(Vector-control)的B16细胞进入C57BL/6小鼠体内,肿瘤生长情况每天用卡尺通过测量肿瘤的长和宽来监控,按照以下公式计算肿瘤体积：volume=(1/2)Lw2,评定肿瘤形成的影响和肿瘤生长率；PCR array分析癌症相关基因。
结果：
1.所用到的生长因子和死亡挑战因子都显著性加强LA向AA的转换,增加了D6D的活性。
2. D6D mRNA表达被生长因子和死亡挑战因子上调,D6D蛋白水平除了在酸性条件(pH 6.5)下没有被提高外,在上面提到的所有因子的作用下都被上调。
3.在B16细胞内PPAR-a被生长和死亡挑战因子显著性提高,个别因子对PPAR-a mRNA表达的调节与相应的D6D表达不成比例。
4.在体外过表达D6D促进B16细胞增长,而敲除D6D则抑制B16细胞增长；在体外过表达D6D促进B16细胞迁移,而敲除D6D则抑制B16细胞迁移。
6.在体内过表达D6D促进B16黑色素瘤生长。
7.与Vector-control组比较,在D6D-over B16组黑色素瘤中AA和PGE2含量较高。
8.肿瘤生成时,抗凋亡基因(bax、bcl-2、bcl-2l1和survivin)、原癌基因(brcal、fos、jun、met和myc)、转录因子(nfkbl和nfkbia)和血管形成相关基因(pdgfa、pdgfb、vegfa、vegfb和vegfc)被上调,而癌症抑制基因pten被下调约64倍。
结论：证明了AA、D6D和PGE2与癌症发生密切相关,D6D可以作为一个新的抗癌靶点。
总之,本研究发现多不饱和脂肪酸参与了肿瘤的发生,D6D的活性和表达量的提高可以促进癌症的发生和迁移,提示D6D可以作为一个新的抗癌靶点。
Identification of specific molecules involved in cancer and the development of inhibitors to block these molecules-targeted therapies-is an exciting and interesting area of current cancer research. polyunsaturated fatty acids (PUFAs) (such as, arachidonic acid, AA) and their metabolites (such as, prostaglandin E2, PGE2) were found in many disease, including cancer. However, how they participate in the cancer cells metabolism and What kind of role play in the metabolism is still not clear. In this study, cancer cell, breast cancer sample and transfer delta-6 dehydrogenase genes in mice model as research object, at the molecular level, cell and animal level, through observing the change of AA, AA metabolites PGE2 and AA synthesis of related desatuarase (D6D) and a series of gene related to the occurrence and the development of cancer, to explore whether D6D correlated with cancerogenesis. This will lay the foundation for further clinical studies in vivo and clinic study. Main research methods and the results are as follows:
1. Effect of anti-cancer drug on PUFAs, their metabolites and related gene in cancer cells
Methods:The proliferation of cells was detected by XTT, and the profile of fatty acids was examined by Gas chromatography (GC). In addition, stearoyl-CoA desaturase-1 (SCD1), delta-5-desaturase (D5D), D6D and cyclooxygenase II (COX-2) mRNA expression were measured by the real-time reverse transcription. D5D and D6D protein expression were measured by Western Blotting.The PGE2 production was determined by enzyme-linked immunosorbent assay.
Results:
a. After being treated with CPT (0.0625-2μM), the Inhibiton ratio of cancer cells gradually increased (P<0.05 or P<0.01); After being treated with Ber (0.0625-2μM), the Inhibiton ratio of cancer cells gradually increased (P<0.05 or P<0.01).
b. After being treated with Ber (8μg/ml or16μg/ml) and CPT (0.25μMor0.5μM), respectively, the percent of PUFAs in these five cancer cell lines change, but the common characteristics is:the chang of AA is significant in all cancer cell lines (P<0.05).
c. Compared to control group, the expression of D5D and D6D mRNA were significantly increased in Ber and CPT treated group (P<0.05 or P<0.01); CPT treated in HT-29 cell group, the expression of SCD1 mRNA were significantly increased (P<0.01); CPT treated in B16 cell group, the expression of SCD1 mRNA were significantly decreased (P<0.05); Ber or CPT treated in other cell groups, the expression of SCD1 mRNA were not changed; Ber and CPT treated in MDA-MB-231, MCF-7 and ZR-75-1 cell group, the expression of COX-2 mRNA were significantly increased (P<0.01); Ber and CPT treated in HT-29 and B16 cell group, the expression of SCD1 mRNA were significantly decreased (P<0.05 or P<0.01).
d. Ber or CPT treated in all cell groups, the expression of D5D and D6D protein were obversely increased.
e. Ber or CPT treated in other four cell groups, the product of PGE2 were raised except for B16 cell.
Conclusions:the improvement of expression of D5D and D6D induced the increase of AA, and the product of PGE2 were obversely raised; the reduce of expression of D5D and D6D induced the decrease of AA, and the product of PGE2 were obversely reduced. This suggests D5D and D6D can be as the biological targets of the found and treatment of cancer biology.
2. Change of D6D in human Breast cancertissue
Methods:the profile of fatty acids was examined by GC. the activity of D6D was measured by the ratio of LA/AA. D6D mRNA expression were measured by the real-time reverse transcription. D5D and D6D protein expression were measured by Western Blotting. The PGE2 production was determined by enzyme-linked immunosorbent assay.
Results:
a. The conversion of LA and ALA, as indicated by the ratio of LA/AA and ALA/EPA, were significantly enhanced in tumor tissues comparing to normal and adjacent tissues, suggest the acivity of D6D was significantly improved.
b. Expression of D6D mRNA was up-regulated by 64 folds and 50 folds in human breast cancer comparing to normal and adjacent tissues; Expression of D6D protein was up-regulated in human breast cancer comparing to normal and adjacent tissues; Expression of D6D mRNA and protein were changed in normal tissues comparing to adjacent tissues.
c. The product of PGE2 was significantly raised in human breast cancer comparing to normal and adjacent tissues; The product of PGE2 was changed in normal tissues comparing to adjacent tissues.
Conclusions:State the up-regulation of activity and expression of D6D induced the increase of AA, at the same time, the product of PGE2 was also obversely improved, suggest D6D can be as the biology target of treating cancer.
3. Role of D6D in vitro and in melanoma growth in vivo
Methods:B16 cell treated with growth factors, including epidermal growth factor (EGF), fibroblast growth factor (FGF), et al, Oxidation reaction type (H2O2), radiation (UV light and X-array), Acidic conditions (pH 6.5) and hypoxia conditions. After B16 cell was treated by these factors, the profile of fatty acids was examined by GC, the activity of D6D was measured by the ratio of LA/AA, D6D and PPARa mRNA expression were measured by the real-time reverse transcription, D6D protein expression were measured by Western Blotting. Inoculate Cancer cells into mouse, tumor growth will be monitored everyday by measuring the length (L) and width (w) of the tumor with a caliper and calculating tumor volume on the basis of the following formula:volume= (1/2)Lw2, to assess he incidence of tumor formation and tumor growth rate. cancer-related genes were analysed by PCR array. The PGE2 production was determined by ELISA,
Results:
a. The activity of D6D is significantly higher in growth and death-challenging factors than in control, and the activity of D6D is increased.
b. The expression of D6D mRNA was up-regulated by growth and death-challenging factors, The expression of D6D protein was up-regulated by growth and death-challenging factors except for Acidic conditions (pH 6.5).
c. PPAR-a was significantly up-regulated in B16 cells by both growth and death-challenging factors, However, the regulation of PPAR-a mRNA expression by individual factors was not proportional to the corresponding levels of D6D expression.
d. Over-expression of D6D promoted B16 cell growth while knock-down of D6D inhibited B16 cell growth in vitro.
e. Over-expression of D6D promoted B16 cell migration while knock-down of D6D inhibited B16 cell migration in vitro.
f. Over-expression of D6D promoted B16 melanoma growth in vivo.
g. AA and PGE2 was higher in D6D-over B16 melanoma than in Vector-control.
h. Expression of several genes that are involved in tumorigenesis, such as anti-apoptotic genes (bax, bcl-2, bcl-211 and survivin), oncogenes (brcal,fos,jun, met and myc), transcriptional factors (nfkbland nfkbia), and angiogenesis related genes (pdgfa, pdgfb, vegfa, vegfb and vegfc) were up-regulated, while the cancer-suppressor gene pten was down-regulated by 64 folds.
Conclusions:Testify AA, D6D and PGE2 Closely related with cancer, and D6D can be used as a new anti-cancer targets.
In summary, the study suggest PUFAs involve in the cancerogenesis and the up-regulation of the activity and expression of D6D can promote cancerogenesis and migration, then, D6D act as a new anti-cancer target.
引文
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