摘要
宫颈癌最常见的女性生殖道恶性肿瘤,发病率和病死率居生殖道恶性肿瘤首位。每年全世界大约有53万新发病例,约50%患者死于该疾病,其中的80%来自发展中国家。早期宫颈癌一般推荐采用手术治疗,对于晚期转移和复发的病例,则失去了手术机会,常规采用化疗和放疗。然而,由于耐药的发生,患者身体耐受状况的恶化,放、化疗效果十分有限。因此,深入探讨宫颈癌发病机制,寻找更为安全有效、靶向性强的宫颈癌防治办法意义重大。
靶向抑制组蛋白脱乙酰化酶(histone deacetylase, HDAC)是一种目前非常有前景的肿瘤治疗手段。组蛋白的乙酰化修饰是一种重要的基因表达调控模式,由HDAC和组蛋白乙酰化转移酶(histone acetyl-transferase, HAT)共同调节。研究证实,脱乙酰化作用过度,导致一系列肿瘤抑制基因下调／沉默,在肿瘤的发生过程起到关键作用；在宫颈癌组织中,HDAC活性异常增高；宫颈脱落细胞学发现组蛋白H3乙酰化水平与宫颈上皮内瘤变(cervival intraepithelial neoplasia, CIN)程度相关。因此,组蛋白脱乙酰化酶抑制剂(histone deacetylase inhibitor, HDACi)是一种潜在的宫颈癌靶向治疗药物。
全反式维甲酸(all-trans retinoic acid, ATRA)是一种上皮细胞生长和分化的调节剂,可以诱导发生转化的细胞重新进入分化程序,而被用于肿瘤的防治。ATRA与受体(retinoic acid receptor, RAR)结合,尤其是RARβ2,才能发挥抗肿瘤作用。RARβ2作为一种重要的肿瘤抑制基因,由于启动子区域的甲基化和／或去乙酰化修饰而在包括宫颈癌在内很多肿瘤中的表达被沉默。有研究报道,HDACi可以上调多种肿瘤RARβ2的表达。因此,HDACi联合ATRA能否重启宫颈细胞RARβ2的表达,并发挥协同抗肿瘤作用值得深入研究。
本课题将分析临床宫颈癌组织中组蛋白乙酰化水平与肿瘤抑制基因(Tumor suppressor genes, TSGs)表达及相关病理参数的关系；深入探讨HDACi (VPA和SAHA)联合ATRA对宫颈癌细胞RARβ2的表达的影响,从表观遗传修饰角度来阐明调控机制；通过体外实验,研究HDACi联合ATRA的抗宫颈癌作用,并深入探讨分子机制；建立人宫颈癌移植瘤模型,进一步评价疗效和验证分子机制。
主要研究结果如下：
1宫颈癌组织中组蛋白乙酰化水平和RARβ2及其下游基因的表达显著降低,甚至缺失：选取高、中、低分化的宫颈鳞癌组织65例,免疫组化检测AcH3、RARβ2、 E-cadherin和β-catenin的表达并评分。结果显示,随着宫颈癌组织分化程度的降低,AcH3、RARβ2、E-cadherin和p-catenin的表达逐渐降低、甚至缺失；组蛋白H3的乙酰化水平与RARβ2、E-cadherin和β-catenin的表达呈显著的正相关性(r=0.560, r=0.731, and r=0.733, P均<0.01)。表明,宫颈癌的进展过程中存在表观遗传修饰的异常,后者可能参与调控肿瘤抑制基因RARβ2. E-cadherin和β-catenin的表达。
2HDACi联合ATRA显著提高宫颈癌细胞株AcH3水平,重启RARβ2表达：HDACi联合ATRA处理宫颈癌细胞株HeLa和SiHa48h后,基因表达谱芯片和Q-PCR结果证实RARβ2表达重启,转录水平显著上调,而RARα和RARγ则为组成性表达；WB显示组蛋白乙酰化水平显著提高,RARβ2表达量显著上升。
3AcH3与RARβ2启动子区域RARE结合,启动RARβ2表达：以往研究证实,组蛋白H3第9位赖氨酸乙酰化与基因转录活化相关。我们采用H3K9ac抗体进行ChIP实验,结果显示HDACi联合ATRA通过提高H3K9ac水平,后者再与RARβ2启动子区RARE结合,从而重启RARβ2表达。
4HDACi联合ATRA显著抑制宫颈癌细胞增殖
1) HDACi联合ATRA抑制宫颈癌细胞增殖能力： MTT实验显示,HDACi与ATRA联合有效抑制宫颈癌细胞增殖,细胞增殖抑制率显著高于VPA和ATRA单一应用(P<0.01),甚至优于1mgL顺铂对宫颈癌细胞的抑制作用(P<0.01)；ATRA对pIRES2-RARβ2-EGFP稳转宫颈癌细胞株的抑制作用与联合用药效果无显著差异(P>0.05),表明HDACi重启宫颈癌细胞RARβ2表达,提供了与ATRA协同抗肿瘤作用的分子基础。药物处理后,Ki67的表达明显减少,细胞集落形成能力被显著抑制,联合用药效果优于任一药物单用(P<0.01),再次验证了HDACi和ATRA的协同／相加抑制宫颈癌细胞增殖的作用。
2) HDACi联合ATRA引起宫颈癌细胞G1期阻滞：HDACi和ATRA处理宫颈癌细胞株48h后检测细胞周期,结果显示联合用药使细胞株发生G1期阻滞；WB结果表明,HDACi和ATRA显著上调P21CIP1和P53的表达,而p-Stat3水平显著降低,Cyclin D1水平仅轻微下调。
3) HDACi联合ATRA诱导宫颈癌细胞分化：细胞进入分化程序前需脱离细胞周期,WB和免疫组化结果证实,HDACi联合ATRA显著提高上皮细胞分化标志物Filaggrin、Loricrin、和Involucrin的表达；FACS和WB结果显示,药物处理后未引起细胞凋亡的显著增加。
4) HDACi联合ATRA通过E-cadherin/PI3K/Akt通路诱导细胞分化：WB显示药物联合处理上调E-cadherin/β-catenin和p-Akt水平；分别采用LE-135拮抗RARβ2、siRNA沉默E-cadherin、LY-294002抑制PI3K活性、和siRNA沉默Akt1/2表达,可以阻断诱导分化作用。表明,HDACi联合ATRA重启RARβ2表达,通过E-cadherin-PI3K/Akt通路诱导宫颈癌细胞分化。
5HDACi联合ATRA抑制裸鼠皮下移植瘤的生长：分别将5×106HeLa和SiHa细胞裸鼠背部皮下注射,建立移植瘤模型。治疗4周后,联合用药显著抑制肿瘤生长,肿瘤体积显著小于VPA组和ATRA组(P<0.01),与顺铂治疗组无显著差异(P>0.05)。与体外实验结果一致,WB显示药物联合处理显著提高组蛋白乙酰化水平,重启宫颈癌细胞RARβ2并上调P21CIP1和P53的表达,而Stat3磷酸化水平显著降低。免疫组化显示,联合药物处理抑制Ki67表达,增强上皮细胞终末分化标志Filaggrin、Loricrin、和Involucrin的表达。
6建立人宫颈癌组织裸鼠皮下移植瘤模型,验证HDACi联合ATRA对宫颈癌的治疗作用
1) HDACi联合ATRA抑制人宫颈癌组织移植瘤的生长：收集人低分化宫颈鳞癌组织,经过裸鼠皮下2次移植建立移植瘤模型。药物治疗4周后,联合用药显著抑制肿瘤生长(P<0.01),对照组、VPA组、ATRA组和联合用药组肿瘤平均体积分别316.65±94.58mm3,119.83±7.74mm3, and208.64±76.61mm3,66.84±19.10mm3；肿瘤抑制率(percentage of tumor-growth inhibition,%TGI)分别为59.39%,37.58%,和73.33%。
2) HDACi联合ATRA诱导移植瘤分化及细胞凋亡：药物治疗4周后,剥离肿瘤组织,HE染色可见联合治疗组出现细胞角化和少量角化珠形成,未见核分裂相,而对照组仍维持来源宫颈癌组织的低分化状态,核分裂相多见。免疫组化显示,HDACi联合ATRA抑制Ki67表达,提高AcH3、RARβ2、及Loricrin、和Involucrin的表达；TUNEL检测显示,VPA治疗后凋亡细胞增加,联合治疗组凋亡细胞增加最为显著(P<0.01)。
3) HDACi联合ATRA通过表观遗传调控机制重启RARβ2而发挥抗肿瘤作用：药物治疗4周后,免疫组化和WB结果表明组蛋白H3乙酰化水平显著提高；ChIP结果显示,H3K9ac可以与RARβ2启动子核心区域RARE结合,从而启动RARβ2的表达；与体外实验结果一致,Q-PCR和WB结果显示重启RARβ2表达后,其下游E-cadherin和上皮细胞分化标志物Involucrin和Loricrin的表达显著上调；同时P21CIP1、P53和活化的Caspase3表达上调,Stat3磷酸化水平显著降低,Bcl2的表达出现下调。
综上所述,HDACi单独和联合ATRA可以通过表观遗传途径重启宫颈癌细胞RARβ2的表达,继而提供了两者协同／相加抗肿瘤作用的分子基础；HDACi联合ATRA使宫颈癌细胞脱离细胞周期,通过E-cadherin/PI3K/Akt通路诱导细胞分化是其抗肿瘤作用的主要机制,细胞凋亡也发挥了一定作用。本研究不仅进一步完善了宫颈癌的发病机制,而且阐明了HDACi联合ATRA对宫颈癌诱导分化治疗的效果及信号途径,为临床宫颈癌的防治提供了新的策略,但是治疗效果还需要通过临床试验进一步验证和评价。
Cervical cancer is one of the most frequent diseases in women and a considerable cause of morbidity and mortality among them. It is the second more frequent type of cancer in women worldwide, preceded only by breast and colorectal cancer; each year approximately500,000women worldwide are diagnosed with invasive cervical cancer and more than half of them die of this disease. Eighty percent of these deaths occur in developing countries. Surgery is the recommended treatment for early-stage cervical cancer, but in advanced stages, namely recurrent and metastatic cases, surgery has very limited value. Additionally, the tumors at advanced stages are commonly resistant to chemotherapy and these patients also frequently have a poor performance status, which limits use of aggressive chemotherapy or radiation. Thus the majority of patients die as a result of uncontrolled disease. Therefore, new therapeutic approaches with fewer adverse effects are needed for cervical cancer.
One targeted class of compounds of particular interest is the histone deacetylase (HDAC) inhibitors. Histone acetylation is a critical regulatory mechanism for gene expression. The aberrant deacetylation of critical genes involved in differentiation, apoptosis or cell cycle arrest has been reported to contribute to the pathogenesis of malignancy. In cervical cancer, it has been reported that HDACs are overexpressed, and the presence of phosphorylated and acetylated forms of histone H3in cytologic smears has demonstrated a marked association of histone H3modifications with the progression of the disease from cervical intraepithelial neoplasia (CIN) I to CIN II and CIN III. HDAC inhibitors are therefore attractive target compounds for cervical cancer treatment.
All-trans retinoic acid (ATRA) is a potent regulator of cellular growth and differentiation, including normal epithelial cell differentiation; it can function as a chemopreventive agent and is an effective inhibitor of chemical and viral carcinogenesis. The antineoplastic pathways induced by ATRA are regulated predominantly by RARβ (particularly the β2isoform). However, the expression of RARβ2is frequently decreased or lost in many cancer types, including cervical carcinomas. Recent studies have shown that the loss of RARβ2is attributed to the silencing of its promoter region due to histone hypermethylation and deacetylation. The use of HDAC inhibitors, alone and in combination with ATRA, has been shown to restore the expression of silenced RARβ2, thus HDAC inhibitors enhance the growth inhibitory and proapoptotic actions of ATRA in many types of cancer cells. Therefore, whether the promising combination of VPA and ATRA results in the reexpression of silenced RARβ2, and consequently has additive effects on growth suppression in cervical cancer cells, merits further investigation.
In this study, we investigated histone H3acetylation and tumor suppressor genes (TSGs) expression in cervical cancer and its association with clinicopathological parameters. The efficacy of combined treatment with HDACi and ATRA was examed in restoring RARβ2expression and anti-neoplastic activity in cervical cancer. Furthermore, we evaluated the therapeutic potential of the HDACi combined with ATRA in treating a tumour xenograft model derived from human cervical carcinoma.
1The expression of AcH3, RARβ2and its downstream genes was downregulated or even silenced. In the65cancerous tissues, the immunoreactivity intensity of these four parameters was strong in well-differentiated tumours and reduced in moderately differentiated carcinoma, with weak or negative labelling in poorly differentiated carcinomas. There was a statistically significant correlation between H3acetylation and the expression of RARβ2, E-cadherin, and β-catenin (r=0.560, r=0.731, and r=0.733,respectively, P<0.01). These indicate that transcriptional silencing by histone deacetylation is one of the well-established mechanisms of tumor suppressor genes inactivation.
2The combination of HDACi and ATRA restores RARβ2expression via increasing the level of acetylated histone H3. In our experiments, an immunoblot analysis showed that HDACi, either alone or combined with ATRA, strongly induced the hyperacetylation of histone H3. Intriguely, the expression of RARJ32was significantly induced, with50-to90-fold upregulation in combination-treated cells but not detected in untreated control cells. We did not detect any differences in the expression of RARa and RARy between the different treatments, but both were constitutively expressed in both cell lines after treatment.
3HDACi in combination with ATRA restore RARβ2expression through RARβ2-RARE. The hyperacetylation of lysine9on histone H3(H3K9ac) is usually associated with actively transcribed genes. To further understand the mechanism for histone acetylation-induced re-expression of RARβ2, we performed a ChIP assay using an anti-H3K9ac antibody to determine the binding of acetylated histone H3to the RAR(32promoter region. This combined treatment was more effective at inducing histone acetylation at the RARβ2-RARE region than any single drug. These results indicate that the RARE in the RARβ2promoter is functional and that histone acetylation at the RARβ2-RARE region is closely correlated with RAR(32re-expression in cervical cancer cells.
4Combined treatment with HDACi and ATRA inhibits the growth of cervical cancer cells.
1) Combined treatment with HDACi and ATRA enhances growth inhibition in cervical cancer cells. The growth inhibition rate of the combined treatment was significantly higher than that of each drug used alone(P<0.01). The effect of the combination drug treatment was even superior to that of the cytotoxic drug cisplatin (1mg/L) administered alone (P<0.01). Furthermore, the combination of HDACi and ATRA exerted additive effects on growth inhibition. The inhibition rate of the cell lines transfected with pIRES2-RARβ2-EGFP treated with ATRA only was similar as that treated with the combination. Consistent with the decreased cell proliferation, the expression of Ki67, a marker for cell proliferation, and colony formation were significantly decreased in cervical cancer cells treated with VPA and ATRA after48h of incubation.
2) Combined treatment with HDACi and ATRA causes G1phase arrest. To assess the specific impact of the combination of HDACi and ATRA on cell proliferation, a flow cytometric analysis of cellular DNA content was performed. An evident G1arrest was observed in cervical cancer cell lines treated with HDACi and ATRA for48h. To determine the causes of the G1phase arrest, we examined the expression of cell cycle regulators (Fig.3B). We observed that VPA combined with ATRA induced an evident up-regulation of P21and P53but a significantly decreased level of p-Stat3expression. However, the expression of cyclin D1was only moderately changed.
3) HDACi potentiates ATRA-induced differentiation in cervical cancer cells. Immunoblotting further confirmed that the combinatorial treatment definitely led to cell differentiation but not apoptosis in the cervical cancer cell lines. Consistent with Annexin V labeling, HDACi alone or in combination with ATRA at the designated concentration induced no major changes in the expression of Bcl-2or Caspase-3and its cleavage products. However, HDACi potentiated ATRA-induced differentiation even at a pharmacological dose of ATRA (1μmol/L) as revealed by the expression of the differentiation markers Filaggrin, Loricrin, and Involucrin.
4) E-cadherin engagement and the activation of the PI3K/Akt pathway determine the differentiation of cervical cancer cells. The above results suggested that when exposed to a combination of HDACi and ATRA, cervical cancer cells exit the cell cycle and undergo differentiation. E-cadherin and phosphorylated Akt was strongly induced by the combination of drugs and continued to increase with up to48h of exposure, which indicates that PI3K/Akt signaling plays a role in the control of cervical cancer cell differentiation. Blocking the PI3K/Akt pathway by either LE135(selective antagonist of RAR02), the PI3K pharmacological inhibitor LY294002, or specific siRNA for E-cadherin and Aktl/2, caused a significantly decreased expression of the terminal differentiation markers Filaggrin, Loricrin, and Involucrin.
5Combined treatment with HDACi and ATRA inhibits the progression of tumor xenografts. Consistently, the combination of VPA and ATRA in vivo caused a statistically significant reduction in tumor volume compared with the single-drug treatments (P<0.01). Importantly, the average tumor volume in the mice that received VPA and ATRA was not significantly different from that of the mice treated with cisplatin alone (P>0.05), suggesting the valid chemotherapeutic potential of this drug combination in cervical cancer. Further, we also found that VPA combined with ATRA induced histone H3hyperacetylation, restored RARβ2expression, and up-regulated P53and P21, whereas this treatment down-regulated p-Stat3in vivo. A pathological examination showed a significant repression of Ki67and the greatest level of induction of the differentiation signature in the combination-treated tumors.
6To evaluate the therapeutic effect of HDACi combined with ATRA on the tumour xenografts derived from human donors.
1) Combined treatment of HDACi and ATRA inhibits the progression of tumour xenografts. To determine the effect of VPA and ATRA on tumor xenograft growth, animals received vehicle as a control, VPA (300mg/kg/d i.p.), ATRA (15mg/kg/d i.g.), or the combination treatment for28days as the tumors were established. After28days, the mean tumor volume for the combination treatment group was66.84±19.10mm3, while the tumor volumes for mice treated with vehicle, VPA, and ATRA were316.65±94.58mm3,119.83±7.74mm3, and208.64±76.61mm3, respectively. These data indicate that the xenografts were suppressed by59.39%,37.58%, and73.33%(percentage of tumor-growth inhibition,%TGI) for the VPA, ATRA, and combined treatments, respectively.
2) Combined treatment of HDACi and ATRA induces cell differentiation and part apoptosis in the tumour xenografts. Importantly, the histological appearance showed that VPA and the combination treatment improved the extent of histological differentiation in the tumor xenografts. Cancer cells from xenografts treated with VPA alone or in combination with ATRA have abundant eosinophilic keratinized cytoplasm, while mitotic figures are absent or noted only occasionally. However, cancer cells in the tissues from both the control and ATRA-treated groups were poorly differentiated. Mitotic figures were common (2-4per high-power field in the control group, but≤2per high-power field in ATRA-treated group), and the cytoplasm was eosinophilic to amphophilic, while keratinization was minimal or absent, similar to the original carcinoma. These observations were further verified by immunohistochemical staining for involucrin and loricrin (markers of terminal epithelium differentiation) in tissues from tumor xenografts. Treatment with VPA in combination with ATRA led to a significant decrease in Ki67-positive cells. In addition to inducing differentiation, VPA also promotes apoptosis. To explore this effect, we performed TUNEL staining to evaluate apoptosis in tumor xenografts. There was a significant increase in apoptotic cells in the combination-treated tumors.
3) HDACi and ATRA restore RARβ2expression via epigenetic modification and sequentially inhibit tumor growth. VPA treatment significantly increased the level of acetylated H3compared to the control and the ATRA group. When combined with ATRA, VPA exhibited an evident additive effect in histone epigenetic modification. The ChIP assay showed that VPA combined with ATRA caused a significant increase in the level of histone acetylation at the RARβ2-promoter region. Therefore, the combination treatment reactivated RARβ2expression via epigenetic modification, sequentially enhancing the expression of target genes, including E-cadherin, Involucrin, and Loricrin. Furthermore, a concomitant increase in the levels of P21CIP1, P53, and activated caspase3as well as a decrease in the levels of p-Stat3and Bcl2were noted.
In conclusion, HDACi in combination with ATRA has additive effects on the inhibition of cell proliferation and on retarding rumor growth in cervical cancer by restoring RARβ2expression via epigenetic modulation and sequentially promoting differentiation through the PI3K/Akt pathway. Based on these results, a therapeutic regimen combining HDACi and ATRA could be useful in the treatment of cervical cancer, but clinical trials are needed to further evaluate the potential of this combination therapy.
引文
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