激活转录因子2及其在肿瘤中的研究进展

激活转录因子2(ATF2)主要通过介导细胞感受外界刺激而调节转录.多项研究显示ATF2参与恶性肿瘤的发生及肿瘤细胞的增殖、分化、凋亡、侵袭及转移等过程的调节.ATF2的激活可促进肿瘤细胞生长,但也有部分报道显示ATF2的激活可抑制肿瘤细胞生长.进一步揭示ATF2在各种肿瘤形成过程中的作用机制,可为肿瘤的病因学研究和治疗学探索提供新的思路.     

软骨肉瘤细胞PTHrP和Sox9及Bc1-2基因表达及其相互作用的研究

目的:研究PTHrP、Sox9和Bc1-2基因在人体软骨肉瘤细胞HTB-94中的相互作用机制.方法:小干扰siRNA阻断PTHrP后,分别检测肿瘤细胞中SOx9、Bc1-2和Co12α1的mRNA及蛋白表迭.结果:PTHrP基因被干扰后,PTHrP基因的mRNA及蛋白表达降低,Sox9、Bc1-2和Co12α1的tuRNA及蛋白表达都受到抑制;而PTHrP基因的干扰作用去除,Sox9、Bc1-2和Co12α1的mRNA及蛋白表达抑制作用也消失.结论:PTHrP基因在肿瘤细胞的抑制引起Sox9、Be1-2和Co12α1肿瘤相关基因的抑制,提示PTHrP基因是Sox9、Be1-2和Co12α1肿瘤相关基因的上游基因.     

软骨肉瘤细胞PTHrP和Sox9及Bcl-2基因表达及其相互作用的研究

目的：研究PTHrP、Sox9和Bcl-2基因在人体软骨肉瘤细胞HTB-94中的相互作用机制。方法：小干扰siRNA阻断PTHrP后,分别检测肿瘤细胞中Sox9、Bcl-2和Col2α1的mRNA及蛋白表达。结果：PTHrP基因被干扰后,PTHrP基因的mRNA及蛋白表达降低,Sox9、Bcl-2和Col2α1的mRNA及蛋白表达都受到抑制;而PTHrP基因的干扰作用去除,Sox9、Bcl-2和Col2α1的mRNA及蛋白表达抑制作用也消失。结论：PTHrP基因在肿瘤细胞的抑制引起Sox9、Bcl-2和Col2α1肿瘤相关基因的抑制,提示PTHrP基因是Sox9、Bcl-2和Col2α1肿瘤相关基因的上游基因。     

微小RNA与乳腺癌细胞的增殖和转移

 乳腺癌的发生是一个多因素参与的阶段性演进过程,微小RNA（miRNA）可通过调节肿瘤细胞的增殖、凋亡和迁移参与肿瘤发生、发展及远处浸润转移。miRNA影响乳腺癌细胞的增殖与转移机制研究将为乳腺癌的诊治提供新的思路。     

miRNA对肿瘤生物学特性的影响

研究显示miRNA与肿瘤发生形成过程及其恶性生物学行为密切相关,作为一种调节分子可能参与了肿瘤的发生以及肿瘤细胞的增殖、分化、细胞凋亡、侵袭和转移及肿瘤耐药等的调节.miRNA靶标及其作用机制的深入研究可为解开肿瘤的发生发展机制及肿瘤治疗策略提供新的思路.     

趋化因子与肺癌

趋化因子是一类趋化细胞定向移动的小分子蛋白,在肺癌中,趋化因子参与调节肿瘤细胞的生长、肿瘤内血管生成、抗肿瘤免疫及诱导远处转移的过程.趋化因子参与了肺癌进展,为肺癌的治疗提供了新的靶点.     

细胞间的相互作用与肿瘤的浸润转移研究进展

肿瘤细胞的浸润转移过程是十分复杂的 ,这一过程包括了一系列的肿瘤细胞与肿瘤细胞、肿瘤细胞与宿主细胞、肿瘤细胞与细胞外基质 (extracellularmatrix ,ECM)间的相互作用 (interaction) ,在多种细胞因子的参与调节下 ,使某些肿瘤细胞能够发生成功的转移或 和迅速的生长。就肿瘤细胞的生物学特性、细胞间的相互作用 ,对肿瘤的浸润转移与术后早期复发的影响研究进展 ,做一系统综述     

BSP和PTHrP的联合检测对乳腺癌骨转移临床意义的研究

目的:探讨骨唾液蛋白(BSP)和甲状旁腺相关蛋白(PTHrP)的联合检测对乳腺癌骨转移的临床意义.方法:乳腺癌87例患者,分为骨转移组40例和无骨转移组47例.应用免疫组织化学法检测石蜡包埋标本BSP和PTHrP的表达.结果:BSP和PTHrP在骨转移组的阳性表达均明显高于无骨转移组(x2值分别为8.47和10.49,P均<0.01),且强阳性表达也均高于后者(x2值分别为9.18和11.05,P均<0.05);同时两者在骨转移组的阳性表达与无转移组和骨外转移组之间比较,差异有统计学意义(P<0.01),而后两组间阳性表达差异无统计学意义(P>0.05).Cox比例风险回归模型分析结果发现,乳腺癌组织中BSP和PTHrP的高表达是预测骨转移的主要危险因素(P<0.01),其相对危险度分别为1.293和1.348.Log-rank生存曲线分析结果显示,在乳腺癌患者中BSP和PTHrP高表达者的累积生存概率均明显低于BSP和PTHrP阴性表达组,P<0.05.结论:BSP和PTHrP的过表达是早期预测乳腺癌骨转移的良好标志,并可作为评估乳腺患者的一项重要的预后因子.     

糖皮质激素受体与肿瘤

糖皮质激素受体(GR)是肿瘤细胞信号传导、相关基因表达和细胞凋亡等多环节中的一个重要调节因素.GR具有自身结构的特殊性及与糖皮质激素(GC)结合的专一性,使其可在转录及翻译水平调节肿瘤相关基因的转录与表达,发挥调节肿瘤细胞代谢的生物学效应.现就此方面研究进展综述如下.     

双氢青蒿素的抗肿瘤作用机制

双氢青蒿素是青蒿的活性成分之一,可通过与铁离子形成自由基杀伤肿瘤细胞、诱导细胞凋亡、抗肿瘤血管生成、抑制肿瘤侵袭转移、逆转多药耐药、影响细胞内Ca2浓度、调控细胞周期、调节细胞自噬和免疫系统等方式参与抗肿瘤过程,是潜在可利用的抗肿瘤新药.     

PTHrP and breast cancer]

Parathyroid hormone-related peptide (PTHrP) has a high homology with the N-terminal portion of the parathyroid hormone (PTH). The gene of PTHrP is complex and can generate by alternative splicing at least three mature peptides containing 139, 141 and 173 amino acids. PTHrP acts via a common receptor with PTH but also via specific receptors. In physiological circumstances, PTHrP is produced locally in many normal tissues where it has autocrine/paracrine functions, particularly during embryonic development, growth regulation and differentiation of many cellular types. PTHrP has endocrine action on bone and kidney. The humoral hypercalcemia of malignancy is mainly mediated by PTHrP. Most hypercalcemic patients with solid tumors have increased plasma PTHrP, whereas PTHrP is not detectable in healthy subjects. During treatment with bisphosphonates, elevated plasma levels of PTHrP are associated with a weak response. PTHrP has also a significant role in the pathophysiology of bone metastases. PTHrP can induce a local osteolysis near the bone metastases, which favours their progression and thus participates in the autocrine regulation of tumor growth. In breast cancer, PTHrP is detected in about 60% of primary tumors and in more than 70% of bone metastases, whereas only 17% of nonbone metastases express PTHrP. A higher expression of PTHrP and its mRNA 1-139, is positively correlated with an invasive tumor phenotype and the development of bone metastases. PTHrP is an effector of transforming growth factor (TGFbeta) in the development and progression of osteolytic bone metastases. TGFbeta, which is released in bone matrix during osteolytic resorption, enhances tumor cells PTHrP production. Then, PTHrP stimulates bone resorption and develops tumor cells metastatic potential. Thus a feedback loop exists between carcinoma cells and the bone microenvironment, leading to a vicious circle.     

Parathyroid hormone-related protein varies with sex and androgen status in nonsmall cell lung cancer

BACKGROUND: In nonsmall cell lung cancer, tumor parathyroid hormone-related protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex-dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells. METHODS: Tumor PTHrP content was measured by immunoassay, and tumor burden was assessed with multiple measures in BEN squamous cell orthotopic lung carcinomas in athymic mice. In addition, lung adenocarcinoma PTHrP messenger RNA (mRNA) values determined by microarray analyses were compared between men and women. Cultured lung cancer cells were assayed for PTHrP after treatment with estradiol or R1881, a synthetic androgen. RESULTS: Lung carcinomas contained approximately 3 times more PTHrP in female mice than in male mice. Similarly, levels of PTHrP mRNA were significantly greater in adenocarcinomas from patients who were women than from patients who were men. Male mice had greater tumor burden than female mice. Androgen treatment reduced PTHrP in 3 lung cancer lines. Estradiol had no effect. Testosterone treatment also reduced lung carcinoma PTHrP in female mice. CONCLUSIONS: Lung carcinomas in females expressed more PTHrP than in males possibly because of negative regulation by androgens in males. Female mice with higher tumor PTHrP content had significantly less tumor burden than male mice, supporting the hypothesis that PTHrP inhibits tumor growth.     

雌激素缺乏对兔关节软骨甲状旁腺激素相关肽表达的影响

目的：研究双侧卵巢切除后雌激素缺乏对兔关节软骨甲状旁腺激素相关肽（PTHrP）表达有何影响。方法：手术切除双侧卵巢造成兔体内雌激素水平下降，8周后取实验组和对照组右股骨髁关节标本。经免疫组化方法检测PTHrP的表达。用光镜和图像分析仪测定软骨中PTHrP阳性细胞百分率和表达强度。结果：卵巢切除组关节软骨PTHrP阳性细胞百分率和表达强度均高于正常关节软骨，两间的差异有统计学意义。结论：雌激素水平对关节软骨PTHrP表达具有调节作用。     

Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP)

Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFκB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFβ and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.     

Significance of the parathyroid hormone-related protein expression in breast carcinoma

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is produced by various neoplasms and is known to be a causative factor of hypercalcemia of malignancy. It has also been suggested to act as a cytokine for tumor progression. The purpose of this study was to clarify the significance of PTHrP expression in breast carcinoma. METHODS: PTHrP expression was examined in 177 surgically resected breast carcinoma specimens by immunohistochemistry using a monoclonal antibody against the for PTHrP, The relationship of PTHrP expression with clinicopathological factors was analyzed and the clinical courses of the patients are reported. RESULTS: Positive PTHrP staining was detected in 113 ( 64%) of the breast tumors. Among the positive cases, 36 (32%) of the tumors clearly showed strong expression. When the PTHrP expression was divided into three categories, a significant positive relationship was found between PTHrP expression and histological grade of tumor. PTHrP expression was also significantly related to bone metastasis but the staining degree of PTHrP was not. The patients with positive PTHrP tended to have poor outcome in proportion to the staining degree. Univariate analysis demonstrated a significantly shorter overall survival for patients expressing PTHrP, and in multivariate analysis showed that PTHrP status and nodal status were associated with a significantly shorter overall survival. CONCLUSION: Our results suggest that PTHrP expression is not only correlated with bone metastasis but is also related to the progression of breast carcinoma, and that overexpression of PTHrP may be a potential prognostic factor for human breast carcinoma.     

Parathyroid hormone-related protein and human papillomavirus in gynecological tumors

The presence of parathyroid hormone-related protein (PTHrP) and human papillomavirus (HPV) in a series of gynecological tumors from 131 unselected patients was examined. PTHrP was localized immunohistochemically using a highly specific rabbit polyclonal anti-serum against PTHrP(1–16). The results confirmed that gynecological malignancies, although rarely associated with humoral hypercalcemia of malignancy (HHM), stained for PTHrP in a majority of the squamous-cell carcinomas (SCC) at all sites, but only in a minority of adenocarcinomas, and then in areas of squamous metaplasia. This included a series of endometrial tumors. Detection of HPV types was achieved using a polymerase-chain-reaction (PCR) detection system enabling the detection of HPV types 6, 11, 16, 18,31,33 and 45. PTHrP production was not directly related to HPV infection, but correlated with the type of tumor.     

Parathyroid hormone-related protein in tumor tissues obtained from patients with humoral hypercalcemia of malignancy

We assessed the relationship between the parathyroid hormone-related protein (PTHrP) and the development of humoral hypercalcemia of malignancy (i.e., hypercalcemia due to the production by solid tumors of hypercalcemic factors) by assaying tumor extracts from hypercalcemic and normocalcemic patients with cancer for immunoreactive PTHrP contents. Immunoreactive PTHrP was demonstrated in extracts of 21 of 22 tumor tissues obtained from 22 patients with humoral hypercalcemia of malignancy. Immunoreactive PTHrP was rarely seen in tumor tissue extracts obtained from 34 normocalcemic patients with cancer and two hypercalcemic patients with cancer with severe bone metastases. Gel filtration studies of tumor extracts revealed a molecular-size heterogeneity of immunoreactive PTHrP. These radioimmunoassay data indicate a close relationship between detection of PTHrP in tumor tissues and the development of humoral hypercalcemia of malignancy.