Metastasis-related miRNAs,active players in breast cancer invasion,and metastasis

Breast cancer is the most common malignancy with the highest incidence among women in the world. Metastasis is the major reason for breast cancer-related deaths. The precise molecular circuitry that governs the metastasis process has not been completely understood. Discoveries of microRNAs (miRNAs) open a new avenue for cancer metastasis research. It has become clear that alterations of miRNA expression contribute to cancer pathogenesis. miRNAs control a wide array of physiological and pathological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis, and metastasis by modulating the expression of their cognate target genes through cleaving mRNA molecules or inhibiting their translation. Some miRNAs are associated with the invasive and metastatic phenotype of breast cancer cell lines or identified in metastatic tumor tissues and lymph nodes. Some miRNAs serve as metastasis suppressors and their expression is frequently downregulated or lost in both breast cancer cell lines and metastatic foci. Some miRNAs are considered to play key roles in the phenotype formation of breast cancer stem cells. This review will focus on recent discoveries related to the miRNAs involved in the metastasis of breast cancer and discuss the implications for the diagnosis, prognosis, and therapeutic strategies of breast cancer.     

微小RNA与胃癌的研究进展

 微小RNA(microRNA,简称miRNA),是一类生物体内源性的非编码小RNA,在转录后水平上对基因的表达进行负调控,导致mRNA的降解或翻译抑制。影响细胞分化、增殖、凋亡、癌变等多个方面,在整个生物发育过程中产生重要的作用,miRNA可以作为癌基因或抑癌基因在胃癌中发挥作用,本文就miRNA在胃癌中的表达及其作用研究进展作一综述。     

MicroRNA gene expression deregulation in human breast cancer

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.     

MicroRNA ‘signature’ during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention

Dysregulated miRNA expression has been associated with the development and progression of cancers, including breast cancer. The role of estrogen (E₂) in regulation of cell proliferation and breast carcinogenesis is well-known. Recent reports have associated several miRNAs with estrogen receptors in breast cancers. Investigation of the regulatory role of miRNAs is critical for understanding the effect of E₂ in human breast cancer, as well as developing strategies for cancer chemoprevention. In the present study we used the well-established ACI rat model that develops mammary tumors upon E₂ exposure and identified a ‘signature’ of 33 significantly modulated miRNAs during the process of mammary tumorigenesis. Several of these miRNAs were altered as early as 3 weeks after initial E₂ treatment and their modulation persisted throughout the mammary carcinogenesis process, suggesting that these molecular changes are early events. Furthermore, ellagic acid, which inhibited E₂-induced mammary tumorigenesis in our previous study, reversed the dysregulation of miR-375, miR-206, miR-182, miR-122, miR-127 and miR-183 detected with E₂ treatment and modulated their target proteins (ERα, cyclin D1, RASD1, FoxO3a, FoxO1, cyclin G1, Bcl-w and Bcl-2). This is the first systematic study examining the changes in miRNA expression associated with E₂ treatment in ACI rats as early as 3 week until tumor time point. The effect of a chemopreventive agent, ellagic acid in reversing miRNAs modulated during E₂-mediated mammary tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemopreventive action of ellagic acid and treatment of breast cancer.     

微RNA在肺癌中的作用

微RNA分子(miRNA,miR)是一类长约18～25个核苷酸的非编码小分子RNA,起内源性RNA干扰作用.微RNA从转录后水平调控上百种靶基因表达,因而能控制广泛的生物学功能,如细胞增殖、分化、凋亡.通过与靶mRNA的3'端非翻译区(3'UTR)结合,抑制mRNA翻译或增加其稳定性而发挥作用.大部分微RNA定位于基因组肿瘤相关的脆性位点、杂合子缺失点、扩增区及常见断裂区,提示与肿瘤的发生关系密切.各种肿瘤中miR-NAs表达上调或下调,可能起致癌或抑癌基因作用.一直以为肿瘤的发生是由一系列致癌基因和抑癌基因突变逐步形成的.随着非编码RNA的发现,此传统观念被改变.研究表明非编码RNA中的成员microRNA对肿瘤形成起重要的调控作用.近来,越来越多的研究探讨不同的miRNA与各种肿瘤的发生发展乃至治疗预后的关系.肺癌位居世界癌症死因之首,其病因学主要是遗传和吸烟引起的后天损伤.对上百种基因的RNA和蛋白质系统分析有助于明确肺癌发生的分子网络.miRNA与肺癌的发生、发展关系密切,可能在肺癌的诊断、治疗及预后监测中发挥重要作用.目前文献报道的与肺癌关系比较密切的miRNA有miRNA-126、miRNA-221、miRNA-222、has-mir-221、miR-17-92簇、miRNA-128b、has-mir-137、has-mir-182、has-mir-372及miRNA-let7家族成员等.本文就这些miRNAs在肺癌的遗传易感性、诊断、侵袭转移、治疗及预后等方面进行综述.     

MicroRNA-9 is associated with epithelial-mesenchymal transition,breast cancer stem cell phenotype,and tumor progression in breast cancer

MicroRNAs (miRNAs) are involved in the progression of breast cancer. Some miRNAs, especially the miR-200 family, miR-9, and miR-155 have been reported to be associated with epithelial-mesenchymal transition (EMT) and breast cancer stem cell (BCSC) phenotypes. This study was designed to evaluate the expression levels of these miRNAs in human breast cancer samples and analyzed their relationship with clinicopathologic features of the tumor including breast cancer subtype, EMT, BCSC phenotype, and prognosis. Expression levels of the miR-200 family, miR-9, and miR-155 were quantified using qRT-PCR. Breast cancer subtype, BCSC phenotype (CD44+/CD24? and ALDH1+), and expression of EMT markers (vimentin expression and E-cadherin loss) were evaluated by immunohistochemistry. miR-9 was more highly expressed in HER2+ and triple-negative subtypes than in luminal subtypes. Its expression level was significantly higher in tumors with high T stage, high histologic grade, p53 overexpression, and high proliferation index. Expression of miR-9 was also higher in tumors showing the CD44+/CD24? phenotype, vimentin expression, and E-cadherin loss. Furthermore, high level of miR-9 expression was found to be an independent prognostic factor for poor disease-free survival of the patients. Expression of miR-200a and miR-141 was highest in luminal A subtype, and miR-155 expression was highest in triple-negative subtype. Although the expression levels of some miR-200 family members and miR-155 showed difference with regard to EMT or BCSC phenotype, they were not associated with patients’ prognosis. In conclusion, overexpression of miR-9 is found in tumors with aggressive phenotypes and is associated with poor prognosis in breast cancer, suggesting that it may serve as a potential biomarker for breast cancer progression and a target for treatment.     

miRNA调节免疫检查点在肿瘤治疗中的研究进展

肿瘤发生和发展的主要机制之一是免疫反应对癌症特异性抗原的沉默,癌症免疫监视的缺陷可能发生在肿瘤进展的任何阶段。肿瘤微环境中,对T淋巴细胞有活化或抑制作用的免疫检查点分子的异常表达可引起肿瘤细胞的免疫耐受或逃逸。靶向免疫检查点分子(如PD-1及其配体PD-L1等)已被证实是治疗多种类型癌症的新方向。微小RNA(miRNAs)在肿瘤微环境中有重要作用,研究表明一些肿瘤中miRNA的表达特异性高,其对免疫应答特别是早期调节有非常重要的作用。因此,miRNA可能成为癌症治疗中调节免疫检查点的理想分子。多种miRNA在癌细胞中异常表达,为癌症治疗提供了新的机遇,但这些miRNA的确切功能及其与免疫检查点分子间的相互作用还在探索阶段。本综述总结了近来关于miRNA作为免疫检查点分子调节剂的研究结果及其在临床实践中治疗癌症的潜在应用。     

miRNA在骨肉瘤中的研究进展

骨肉瘤是一种恶性程度很高的原发性骨肿瘤,其发生率约为0．04～0．05／万,多数起源于骨间叶细胞,好发部位为长骨,一般为股骨远端或胫骨近端,其次为肱骨近端。好发于10～20岁的青少年,占骨恶性肿瘤的20％左右,肺转移是其主要死亡原因,随着新辅助化疗、保肢手术等的开展,5年生存率提高到近60％～70％。但由于化疗耐药性等问题的存在,患者仍面临着复发及肺转移的困扰。基因治疗、免疫治疗和分子靶向治疗等生物治疗技术的发展也为骨肉瘤的治疗开辟了新的道路,为骨肉瘤患者带来希望。     

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.     

Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors

Aberrant activation of the Wnt signaling pathway plays an important role in the development of solid tumors such as breast and colon cancer. Secreted Frizzled-related protein 1 (SFRP1) is a negative regulator of the Wnt pathway. It has been described that SFRP1 mRNA is strongly down-regulated in breast cancer and a putative tumor suppressor function has been postulated. We have generated and characterized an SFRP1 specific antibody to analyze its expression on protein level and to investigate the association of SFRP1 expression with clinicopathological parameters and patient survival. Analysis of >2000 invasive breast tumors and 56 carcinoma in situ revealed similar frequencies of SFRP1 loss in these tumors (46% and 43% respectively). Therefore, we propose that loss of SFRP1 expression is an early event in breast tumorigenesis. SFRP1 expression was inversely correlated with tumor stage (p<0.001) but not with tumor grade (p=0.14) or lymph node status (p=0.84). Performing a multivariate analysis we could confirm the association between tumor stage and SFRP1 expression (p=0.029). In particular, loss of SFRP1 expression in early stage breast tumors (pT1) was associated with poor prognosis (p=0.04). In conclusion, expression of SFRP1 is commonly lost in breast cancer. SFRP1 expression might be useful as a novel prognostic marker in early stage breast cancer.     

miR-218与宫颈癌关系的研究进展(英文)

MicroRNAs (miRNAs) are small endogenous non-coding RNAs which can specifically silence gene expression, and thereby alter cell and organism phenotype. Deregulation of miRNA expression has been discovered in a variety of tumors and it is now clear that they contribute to cancer development and progression. Previous studies have indicated that miRNAs are involved in developmental timing, cell proliferation, apoptosis, morphogenesis [1] , antiviral defense [2] , and tumorigenesis [3] . In cancer pathways, altered expression of tumor suppressive or oncogenic miRNAs can disrupt regulatory mechanisms normal. Altered miRNAs expression patterns have been observed in a variety of diseased tissues. Cervical cancer is the most common malignant tumor in female reproductive tract. Recently more and more study showed a large number of miRNAs were down-regulated or up-regulated in cervical cancer. Recent data revealed that miRNA-218 (miR-218) played important roles in tumor initiation and development. This review focuses on analysis of miR-218 and will provide some insight into the progress of cervical cancer.     

microRNA在乳腺癌诊断及预后判断中的作用

乳腺癌是全球女性患病率最高的恶性肿瘤,严重危害广大女性的健康。微小RNA(microRNA,miRNA)是一类小的内源性非编码RNA,通过与mRNA 3’端非翻译区部分互补配对,在翻译后水平调节靶基因的表达。miRNA在乳腺的发育过程中发挥多种作用,其表达异常可能导致乳腺癌的发生。乳腺癌中miRNA的异常表达,以及miRNA在血清中的稳定存在,使miRNA有望成为新的生物标志物用于乳腺癌的诊断及预后判断。     

Clinical significance of miR-155 expression in breast cancer and effects of miR-155 ASO on cell viability and apoptosis

Accumulating evidence shows that mircroRNAs (miRNAs) play a vital role in tumorigenesis. miR-155 is one of the most multifunctional miRNAs whose overexpression has been found to be associated with different types of cancer including breast cancer. To further determine the potential involvement of miR-155 in breast cancer, we evaluated the expression levels of miR-155 by real-time PCR and correlated the results with clinicopathological features. Matched non-tumor and tumor tissues of 42 infiltrating ductal carcinomas and 3 infiltrating lobular carcinomas were analyzed for miR-155 expression by real-time PCR. Further, we used an antisense technique to inhibit miR-155 expression in vitro. WST-8 test was performed to evaluate cell viability and apoptosis assay was used to investigate the effect of the miR-155 antisense oligonucleotide (miR-155 ASO) on HS578T cell death. The expression levels of miR-155 were significantly higher in tumor tissues than the levels in matched non-tumor tissues (P<0.001). Up-regulated miR-155 expression was associated with lymph node positivity (P=0.034), higher proliferation index (Ki-67 >10%) (P=0.019) and advanced breast cancer TNM clinical stage (P=0.002). Interestingly, we next found that miR-155 expression levels had close relations with ER status (P=0.041) and PR status (P=0.029). Transfection efficiency detected by flow cytometry was higher than 70%, the WST-8 test showed that viability of HS578T cells was greatly reduced after transfection with miR-155 ASO compared with the scramble (SCR) group or the liposome group. The Annexin V-FITC/PI assay also indicated that transfection with miR-155 ASO promoted apoptosis.