HIF-1α信号通路在肿瘤细胞调控中的研究进展

缺氧诱导因子(HIF-1α)是肿瘤细胞生长过程中重要的调控因子,研究其作用机制有利于实现对肿瘤细胞增殖的抑制作用。HIF-1α可引起多种基因转录,使肿瘤细胞耐受低氧环境,进而使癌症患者在治疗过程中产生耐受反应,最终影响治疗效果,甚至放弃治疗。因此,以HIF-1α为靶点是治疗肿瘤的重要手段和方法。本文对HIF-1α的基本概况及其主要信号通路(PI3K通路、HSP90通路及MAPK通路)以及不同通路抑制剂(如LY294002、17AAG、PD98059、U0126、SB203580、SP600125等)进行综述,并对HIF-1α的应用前景进行展望。     

HIF-1alpha在乳腺癌中的表达及临床意义

目的：分析乳腺癌患者HIF-1alpha的表达水平与临床病理的关系,探讨HIF-1alpha表达水平对于乳腺癌诊治的意义。方法：选取我 院收治的乳腺癌患者共46 例作为实验组,随机选取同期收治的42 例乳腺良性病变患者作为对照组,所有患者均采取手术治疗, 手术中留取病变的乳腺组织,应用免疫组织化学法对乳腺组织中的HIF-1alpha表达水平进行检测,同时分析HIF-1alpha表达水平与乳 腺癌临床病理特征的相关性,并应用统计学软件对结果进行分析。结果：①实验组患者病变乳腺组织中HIF-1alpha表达水平（95.65 %）显著高于对照组（2.50 %）,差异具有显著性（P<0.05）;②HIF-1alpha表达水平与乳腺癌的患者的年龄、肿瘤直径以及雌激素受体状 态无显著相关（P＞0.05）;③HIF-1alpha表达水平与乳腺癌的临床分期、组织学分级以及淋巴结转移情况具有显著相关性（P<0.05）。结 论：乳腺癌患者的HIF-1alpha表达异常升高,其表达水平与癌组织分级、分期以及淋巴结转移情况密切相关,对预后不良具有一定的 提示作用,值得临床深入探讨。     

TGF-beta1、HIF-1alpha、VEGF在胃癌组织及癌旁组织中的表达及临床意义

目的：研究TGF-beta1（转化生长因子-beta1）、HIF-1alpha（低氧诱导因子-1alpha）、VEGF（血管内皮生长因子）在胃癌组织及癌旁组织中 的表达及临床意义。方法：选取于我院就诊的160 例胃癌手术患者切除的组织,采用免疫组化技术检测手术切除的胃癌组织中的 TGF-beta 1、HIF-1alpha及VEGF的表达,分析其与患者临床病理参数的关系。结果：免疫组化结果显示：TGF-beta1、HIF-1alpha及VEGF 在胃 癌组织中的表达均高于癌旁组织,差异均有统计学意义（P<0.05）;TGF-beta1、HIF-1alpha及VEGF 的表达均与肿瘤分期、淋巴结转移及 浸润深度有关（P<0.05）;VEGF的表达分别与TGF-beta1、HIF-1alpgha的表达呈相关关系（P<0.05）。结论：TGF-beta1、HIF-1alpha及VEGF在胃 癌组织中的表达与胃癌的病理学特征有关,检测TGF-beta1、HIF-1alpha及VEGF的表达将有助于临床诊治胃癌患者。     

低氧诱导因子-1在脑损伤中的双向调节作用

低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)作为目前发现的具有高度特异性感受细胞氧分压的调节因子,在脑损伤发生、发展过程中发挥着重要的双向调节作用。HIF-1在轻度和中度脑损伤过程中可以增加神经细胞耐受,促进存活;在重度损伤时,参与细胞凋亡途径,促进神经细胞死亡,在脑损伤中发挥重要作用。对HIF-1及其信号通路的深入研究可为脑损伤的治疗提供药物作用靶点,有重要的理论研究和实用价值。现就HIF-1的结构、功能及在脑损伤中的调节作用进行综述,为临床治疗脑损伤提供参考。     

缺氧诱导因子1α、血管内皮生长因子和成纤维细胞生长因子在胰腺癌中的表达及意义

目的：研究胰腺癌组织中缺氧诱导因子1alpha（Hypoxia-inducible factor-1alpha,HIF-1α）、血管内皮生长因子（vascular endothelial growth factor,VEGF）和成纤维细胞生长因子（fibroblast growth factor,FGF）的表达并探讨其意义。方法：Western blot法检测22例胰腺癌及癌旁组织中HIF-1α、VEGF和FGF蛋白的表达,分析HIF-1α与VEGF、FGF之间的相关性以及与性别、年龄、肿瘤大小、淋巴结转移和TNM分期之间的关系。结果：HIF-1α、VEGF和FGF在胰腺癌组织中的蛋白表达水平明显高于胰腺癌周组织（P〈0.01）,HIF-1α与VEGF、FGF之间的表达具有显著相关性（P〈0.01）。HIF-1α的表达与胰腺癌的TNM分期、肿瘤大小和淋巴结转移有关（P〈0.01）,VEGF和FGF的表达与胰腺癌的肿瘤大小和淋巴结转移有关（P〈0.05）。结论：HIF-1α可以上调VEGF和FGF的表达,在胰腺癌的发生、发展中起着重要作用。     

硫氧还蛋白：一个肿瘤治疗的新靶点

硫氧还蛋白1（Thioredoxin-1,Trx-1）在多种肿瘤细胞和组织中均有过量的表达,它可以调节肿瘤细胞中凋亡通路、转录因子和某些功能蛋白酶的活性,进而影响着肿瘤的发生、发展、增殖、凋亡及血管发生等生理过程。而且,过量表达的Trx-1导致肿瘤细胞对多种治疗药物产生耐药性。近年来Trx-1已成为肿瘤研究的热点,是一个极有价值的肿瘤治疗的新靶点。     

低氧条件下低氧诱导因子1α/miR-210调节回路对肿瘤能量代谢及血管生成的调控

低氧诱导因子1(HIF-1)是低氧下肿瘤细胞信号通路的核心调控因子,研究表明与HIF-1生物学调控功能(血管生成、能量代谢、细胞增殖、细胞凋亡和侵袭转移等)起协同作用的是mi R-210,mi R-210受低氧及HIF-1α调控而表达上调,反之上调的mi R-210又增强HIF-1α分子稳定性,由此两者共同构成HIF-1α/mi R-210调节回路,对肿瘤细胞多种生物学行为进行精确调控,本文对HIF-1α/mi R-210调节肿瘤能量代谢及血管生成两方面做一简要综述。     

胶质瘤p53、PTEN和IDH与HIF-1α的相关性

胶质瘤是最常见的中枢神经系统肿瘤。利用分子生物学技术已确认在胶质瘤存在一种或多种基因表达异常,参与肿瘤的发生发展。缺氧是胶质瘤中普遍存在的现象。缺氧诱导因子1α(HIF-1α)是参与缺氧环境下肿瘤适应性调节的关键转录因子,对维持肿瘤细胞的能量代谢、血管生成、增殖和转移起着重要作用。阐明胶质瘤中重要基因标记物与HIF-1α的相关性可能对胶质瘤的个体化治疗具有参考价值。现对胶质瘤中p53、PTEN和IDH与HIF-1α相关性进行综述。     

HIF-1-alpha激活的长链非编码RNA-ANRIL与肺腺癌的关系的研究

摘要目的：现已经证实缺氧诱导因子-1alpha（hypoxia inducible factor-1,HIF-1alpha）与肺腺癌（lung adenocarcinoma，LA）侵袭性有关。 INK4 基因座中反义非编码RNA（CDKN2B antisense RNA 1，ANRIL）是目前确认的能够促进肿瘤发生发展的一种长链非编码 RNA（long noncoding RNA，lncRNA）。而本研究即探究在肺腺癌中HIF-1琢与ANRIL之间是否存在一定的联系。方法：利用实时定 量PCR 技术（quantitative real-time polymerase chain reaction，qRT-PCR）检测人体肺腺癌组织和肺腺癌细胞系A549 中HIF-1-alpha和 ANRIL的表达水平，然后利用小干扰RNA（small interfering RNA，siRNA）和基因过表达技术使HIF-1alpha低量和过量表达，再检测 肺腺癌细胞系A549 中ANRIL表达水平的变化。结果：ANRIL和HIF-1alpha在人体肺腺癌组织和肺腺癌细胞系A549 中的表达水平 呈现正相关，而且ANRIL 和HIF-1alpha在癌组织中的表达水平均高于癌旁组织，并且通过HIF-1alpha的低量和过量表达，ANRIL亦呈 现相应的变化。结论：ANRIL 和HIF-1alpha在肺腺癌组织中的表达具有相关性，而且HIF-1琢能够刺激激活ANRIL的表达，因此 ANRIL-HIF-1alpha可能为肺腺癌的诊疗提供一个崭新的靶点。     

RNAi技术沉默HIF-1α基因表达的研究进展

缺氧诱导因子-1α（HIF-1α）是一种缺氧诱导的最关键的转录因子,参与细胞的生长、分化和凋亡的调节。在人类实体肿瘤中普遍存在HIF-1α的过表达,并与肿瘤的侵袭、转移、耐药及预后差有关。RNAi干扰技术可敲除目的基因,导致基因功能缺失性变化,已被广泛应用于生命科学研究的各个领域,包括HIF-1α基因功能的研究。各种不同的RNAi技术能有效的特异性地敲除HIF-1α基因的表达,在非肿瘤细胞和肿瘤细胞的HIF-1α基因功能的研究上均有很好的应用,成为研究HIF-1α基因功能的重要的方法之一。     

Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells

Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.     

TORC1 is essential for NF1-associated malignancies

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.     

Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha

Stromal-derived factor-1 (SDF-1) is a unique ligand of the CXC chemokine receptor 4 (CXCR4), which is critically involved in the metastasis of breast cancer. High levels of SDF-1 in the common destination organs of metastasis, such as the lymph nodes, lungs, liver, and bones, attract CXCR4-positive tumor cells. The interaction between SDF-1 and CXCR4 leads to the activation of specific signaling pathways, allowing for homing and metastatic progression. However, regulation of CXCR4 expression at the metastatic organ site is not well-documented. We detected the expression of CXCR4 and hypoxia inducible factor (HIF)-1alpha in breast tumor tissues by immunohistochemical staining and analyzed SDF-1 in primary tumors and lymph nodes using real-time RT-PCR. Compared to the corresponding metastasized tumors in the lymph nodes, primary invasive carcinomas showed more intense staining for CXCR4, particularly on the cellular membrane. Both primary tumors and lymph node metastases exhibited higher levels of CXCR4 expression compared to non-neoplastic breast tissues. Therefore, we hypothesized that the tumor environment in the lymph nodes may cause the reduction of CXCR4 levels in the metastatic tumor cells because of: (1) high SDF-1 levels and (2) lower levels of HIF-1alpha. Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway. In addition, lower levels of HIF-1alpha in the lymph node metastases, probably induced by the less hypoxic environment, further lowered CXCR4 levels. These results indicate that ligand-dependent degradation and lower HIF-1alpha levels may be potential causes of lowered levels of CXCR4 in the lymph nodes compared to the primary tumors. Our study suggests that CXCR4 levels in tumor cells are regulated by its microenvironment. These findings may enhance our ability to understand the biological behavior of breast cancers.     

E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis

The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.     

Development of Lymphoproliferative Diseases by Hypoxia Inducible Factor-1alpha Is Associated with Prolonged Lymphocyte Survival

Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.