环状RNA的结构和功能特性及其与胃癌发生的关系

环状RNA是一类新发现以共价键形成环状结构的RNA分子,没有5'帽和3'尾,具有高度的序列保守性和稳定性,不易被核酸外切酶降解,在转录或转录后水平发挥基因表达调控的作用。近年来,已发现环状RNA与许多肿瘤包括胃癌发生密切相关。首先介绍环状RNA形成、分类、分子特征和功能,然后从环状RNA与胃癌发生、环状RNA与胃癌诊断、以及环状RNA在胃癌治疗中的作用等三个方面阐述环状RNA与胃癌的关系。     

环状RNA及其在结直肠癌中的相关研究

环状RNA是长链非编码RNA的一种特殊类型,是首尾共价闭合环化而形成的环状RNA分子,在生理和疾病过程中具有特殊的生物学功能。环状RNA与肿瘤的发生发展关系密切,其高度稳定性及特异性使其有希望成为恶性肿瘤潜在的生物标志物和新的治疗靶点。目前仅有少量关于环状RNA在结直肠癌中的生物学功能及其相关调控机制的研究报道。本文拟从环状RNA的形成、生物学特征、生物学功能以及其结直肠癌中的相关研究等方面进行简要综述。     

环状RNA翻译在癌症中的研究进展

环状RNA是一类有着独特环状结构的非编码RNA,它在生物体内有微小RNA分子海绵、蛋白质脚手架、调控基因转录、调控可变剪接、进入外泌体等多种经典功能机制。虽然环状RNA被定义成一种非编码RNA,但随着生物信息学和翻译组学的发展与应用,越来越多的研究发现,环状RNA是能够被翻译的。该文介绍了现在主要的环状RNA翻译的调控机制,总结了目前研究环状RNA翻译的常用数据库,汇总了环状RNA翻译的蛋白质和多肽在癌症中的最新发现,讨论了环状RNA翻译的应用前景和问题,旨在促进发现更多由环状RNA编码的与肿瘤相关的蛋白质和多肽。     

环状RNA在肝细胞癌中的作用及机制

肝细胞癌（hepatocellular carcinoma,HCC）治疗困难、预后很差,是肿瘤相关死亡中的第4大癌症,严重危害人类生命健康,但其具体发病机制却仍未完全阐明。因此,探索能调控肝细胞癌发生发展,作为肝细胞癌的诊断标志物或能预测患者预后的关键分子仍十分必要。环状RNA是前体mRNA通过反向剪接产生的由3′, 5′ 磷酸二酯键首尾连接形成的共价闭合环状结构,主要有外显子circRNA（exonic circRNA,ecircRNA）、环状内含子RNA（circular intronic RNA,ciRNA）及外显子 内含子circRNA（exon-intron circRNA,EIciRNA）三大类。由于环状RNA具有普遍性、高度保守性和稳定性,其可以参与多种癌症的发生发展过程,并且可作为肿瘤的早期诊断标志物及预后因子,因此,这是一类新型且非常有潜力应用于临床诊治各阶段的分子。近年来,有大量关于环状RNA与肝细胞癌的研究。这些研究表明,环状RNA在肝细胞癌发生发展进程中发挥的作用十分重要,并且其机制多样。因此,本文主要关注环状RNA在肝细胞癌中的最新进展,总结不同环状RNA分子对于肝细胞癌细胞恶性表型、肿瘤干细胞及肿瘤微环境中免疫细胞的作用,以及其在肝细胞癌临床转移、分期、诊断、预后等各阶段中发挥的功能及其具体作用机制。此外,本文还提出了目前研究中存在的一些问题和不足,以期为未来的研究提供一些新的思路及策略。     

环状RNA的生物学功能及其在肿瘤发生中的作用

近年来,随着RNA研究技术的进步,研究者们在多种生物中发现了数量众多的环状RNA,且发现它们具有重要的生物学功能。环状RNA来源于内含子或外显子,可以充当微小RNA海绵,还能与蛋白质相结合,从而参与基因表达调控并影响蛋白质的功能,此外,个别环状RNA甚至能编码蛋白质。更重要的是,环状RNA在肿瘤(如:胃癌、肝癌、结直肠癌、乳腺癌、宫颈癌和卵巢癌等)的发生和发展过程中起着重要的调控作用。因此,环状RNA有希望成为肿瘤诊断的标志物和治疗的新靶点。     

环状RNA在肝细胞癌中的作用及机制

肝细胞癌（hepatocellular carcinoma,HCC）治疗困难、预后很差,是肿瘤相关死亡中的第4大癌症,严重危害人类生命健康,但其具体发病机制却仍未完全阐明。因此,探索能调控肝细胞癌发生发展,作为肝细胞癌的诊断标志物或能预测患者预后的关键分子仍十分必要。环状RNA是前体mRNA通过反向剪接产生的由3′, 5′ 磷酸二酯键首尾连接形成的共价闭合环状结构,主要有外显子circRNA（exonic circRNA,ecircRNA）、环状内含子RNA（circular intronic RNA,ciRNA）及外显子 内含子circRNA（exon-intron circRNA,EIciRNA）三大类。由于环状RNA具有普遍性、高度保守性和稳定性,其可以参与多种癌症的发生发展过程,并且可作为肿瘤的早期诊断标志物及预后因子,因此,这是一类新型且非常有潜力应用于临床诊治各阶段的分子。近年来,有大量关于环状RNA与肝细胞癌的研究。这些研究表明,环状RNA在肝细胞癌发生发展进程中发挥的作用十分重要,并且其机制多样。因此,本文主要关注环状RNA在肝细胞癌中的最新进展,总结不同环状RNA分子对于肝细胞癌细胞恶性表型、肿瘤干细胞及肿瘤微环境中免疫细胞的作用,以及其在肝细胞癌临床转移、分期、诊断、预后等各阶段中发挥的功能及其具体作用机制。此外,本文还提出了目前研究中存在的一些问题和不足,以期为未来的研究提供一些新的思路及策略。     

EZH2和Ki67的高表达指示三阴性型乳腺癌的发生风险

探讨EZH2和Ki67表达与三阴性型乳腺癌的关系。根据新型乳腺癌分子分型标准,将乳腺癌进行分子分型;免疫组织化学方法检测乳腺癌组织石蜡切片中EZH2和Ki67的表达;采用χ~2检验分析EZH2和Ki67的表达与临床病理参数以及三阴性型乳腺癌的关系。126例乳腺癌患者中,luminal A型、luminal B型、Her-2过表达型和三阴性型分别有39例、30例、21例和36例。36例三阴性型乳腺癌患者中,EZH2高表达者30例(83.33%),Ki67高表达者30例(83.33%);90例非三阴性型乳腺癌患者中,EZH2高表达者33例(36.67%),Ki67高表达者36例(40.00%);与非三阴性型乳腺癌相比,三阴性型乳腺癌中出现EZH2和Ki67高表达的概率较大。EZH2和Ki67高表达与三阴性型乳腺癌具有相关性,EZH2和Ki67可能是三阴性型乳腺癌的判定指标。     

环状RNA在巨噬细胞中的作用

环状RNA(circular RNA, circRNA)是一类特殊的非编码RNA类型,在真核生物细胞和人体转录本中大量存在。circRNA是由前体信使RNA(pre-mRNA)反向剪接形成的共价闭合环状RNA分子,通过充当微核糖核酸(microRNA, miRNA)"海绵"、与蛋白质结合、参与基因转录调控和蛋白质翻译等发挥其生物学作用。随着对circRNA研究的日益增多,已有研究人员报道了circRNA在免疫细胞中的作用。现对circRNA的形成、分类、生物学特性、功能及其在巨噬细胞中的作用作一概述。     

血小板环状 RNA研究进展

血小板环状RNA (platelet circular RNA, platelet circRNA)是一类在血小板中由RNA反向剪切封闭形成的环形RNA分子,具有结构稳定、丰度高以及细胞、组织特异性.血小板环状RNA可以参与细胞内RNA调控网络,与疾病的发生和发展密切相关,可能成为新型的生物标记物及治疗靶点.近年来,关于血小板环状RNA产生、调控、生物学特性、功能及其与疾病的关系等均取得了初步的研究进展.本文将对血小板环状RNA的研究进展予以综述.     

外泌体源性环状RNA在肺癌病理进程及诊疗中的研究进展

外泌体是具有细胞间信号传递生物学功能的一种脂质双分子层囊泡,其内包含RNA、DNA、蛋白质等生物分子,近年来其在疾病发生发展、早期诊断和治疗等方面的作用被广泛研究。环状RNA (circular RNA, circRNA)是一类可以存在于外泌体中的单链闭合环状RNA。越来越多的研究表明外泌体源性circRNA与肺癌的发生发展密切相关,为了更好地了解外泌体源性circRNA在肺癌病理进程中的作用,本文重点讲述了外泌体源性circRNA在肺癌增殖、侵袭与转移、免疫逃逸和耐药中的作用,以及其在肺癌诊断、预后评估及治疗方面的研究进展。     

Prevalence of Papillomaviruses,Polyomaviruses, and Herpesviruses in Triple-Negative and Inflammatory Breast Tumors from Algeria Compared with Other Types of Breast Cancer Tumors

Background

The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC) and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups.

Materials and Methods

One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria) to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses) using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology.

Results

Viral DNA was found in 22 (17.9%) of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type) than non-IBC tumors (30% vs. 13%, p<0.04). Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009).

Conclusions

Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative). While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings.     

Therapeutic options for triple-negative breast cancers with defective homologous recombination

Breast cancer is the most common malignancy among women in developed countries, affecting more than a million women per year worldwide. Over the last decades, our increasing understanding of breast cancer biology has led to the development of endocrine agents against hormone receptor-positive tumors and targeted therapeutics against HER2-expressing tumors. However, no targeted therapy is available for patients with triple-negative breast cancer, lacking expression of hormone receptors and HER2. Overlap between BRCA1-mutated breast cancers and triple-negative tumors suggests that an important part of the triple-negative tumors may respond to therapeutics targeting BRCA1-deficient cells. Here, we review the features shared between triple-negative, basal-like and BRCA1-related breast cancers. We also discuss the development of novel therapeutic strategies to target BRCA1-mutated tumors and triple-negative tumors with BRCA1-like features. Finally, we highlight the utility of mouse models for BRCA1-mutated breast cancer to optimize (combination) therapy and to understand drug resistance.     

Molecular Characteristics and Metastasis Predictor Genes of Triple-Negative Breast Cancer: A Clinical Study of Triple-Negative Breast Carcinomas

Background

Triple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible.

Methodology/Principal Findings

Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04–5.06, Cox P = 0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-β signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer.

Conclusions/Significance

Gene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene signature was found to be statistically predictive in disease recurrence of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant recurrence for early-stage triple-negative patients.     

Comparison of Pathologic Response Evaluation Systems after Anthracycline with/without Taxane-Based Neoadjuvant Chemotherapy among Different Subtypes of Breast Cancers

Purpose

Several methods are used to assess the pathologic response of breast cancer after neoadjuvant chemotherapy (NAC) to predict clinical outcome. However, the clinical utility of these systems for each molecular subtype of breast cancer is unclear. Therefore, we applied six pathologic response assessment systems to specific subtypes of breast cancer and compared the results.

Patients and Methods

Five hundred and eighty eight breast cancer patients treated with anthracycline with/without taxane-based NAC were retrospectively analyzed, and the ypTNM stage, residual cancer burden (RCB), residual disease in breast and nodes (RDBN), tumor response ratio, Sataloff’s classification, and Miller—Payne grading system were evaluated. The results obtained for each assessment system were analyzed in terms of patient survival.

Results

In triple-negative tumors, all systems were significantly associated with disease-free survival and Kaplan-Meier survival curves for disease-free survival were clearly separated by all assessment methods. For HR+/HER2- tumors, systems assessing the residual tumor (ypTNM stage, RCB, and RDBN) had prognostic significance. However, for HER2+ tumors, the association between patient survival and the pathologic response assessment results varied according to the system used, and none resulted in distinct Kaplan—Meier curves.

Conclusion

Most of the currently available pathologic assessment systems used after anthracycline with/without taxane-based NAC effectively classified triple-negative breast cancers into groups showing different prognoses. The pathologic assessment systems evaluating residual tumors only also had prognostic significance in HR+/HER2- tumors. However, new assessment methods are required to effectively evaluate the pathologic response of HR+/HER2+ and HR-/HER2+ tumors to anthracycline with/without taxane-based NAC.     

Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

Introduction

The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75–95% of estrogen receptor (ER)-positive and 40–70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.

Materials and Methods

Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action.

Results

Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.

Conclusion

1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.     

Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study

Background

Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive. It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity.

Methods and Findings

In case-control and case-series analyses, we examined serum concentrations of 25-hydroxyvitamin D (25OHD) in relation to breast cancer prognostic characteristics, including histologic grade, estrogen receptor (ER), and molecular subtypes defined by ER, progesterone receptor (PR) and HER2, among 579 women with incident breast cancer and 574 controls matched on age and time of blood draw enrolled in the Roswell Park Cancer Institute from 2003 to 2008. We found that breast cancer cases had significantly lower 25OHD concentrations than controls (adjusted mean, 22.8 versus 26.2 ng/mL, p<0.001). Among premenopausal women, 25OHD concentrations were lower in those with high- versus low-grade tumors, and ER negative versus ER positive tumors (p≤0.03). Levels were lowest among women with triple-negative cancer (17.5 ng/mL), significantly different from those with luminal A cancer (24.5 ng/mL, p = 0.002). In case-control analyses, premenopausal women with 25OHD concentrations above the median had significantly lower odds of having triple-negative cancer (OR = 0.21, 95% CI = 0.08–0.53) than those with levels below the median; and every 10 ng/mL increase in serum 25OHD concentrations was associated with a 64% lower odds of having triple-negative cancer (OR = 0.36, 95% CI = 0.22–0.56). The differential associations by tumor subtypes among premenopausal women were confirmed in case-series analyses.

Conclusion

In our analyses, higher serum levels of 25OHD were associated with reduced risk of breast cancer, with associations strongest for high grade, ER negative or triple negative cancers in premenopausal women. With further confirmation in large prospective studies, these findings could warrant vitamin D supplementation for reducing breast cancer risk, particularly those with poor prognostic characteristics among premenopausal women.     

Stat1 and CD74 overexpression is co-dependent and linked to increased invasion and lymph node metastasis in triple-negative breast cancer

Triple-negative breast cancer is difficult to treat because of the lack of rationale-based therapies. There are no established markers and targets that can be used for stratification of patients and targeted therapy. Here we report the identification of novel molecular features, which appear to augment metastasis of triple negative breast tumors. We found that triple-negative breast tumors can be segregated into 2 phenotypes based on their genome-wide protein abundance profiles. The first is characterized by high expression of Stat1, Mx1, and CD74. Seven out of 9 tumors from this group had invaded at least 2 lymph nodes while only 1 out of 10 tumors in group 2 was lymph node positive. In vitro experiments showed that the interferon-induced increase in Stat1 abundance correlates with increased migration and invasion in cultured cells. When CD74 was overexpressed, it increased cell adhesion on matrigel. This effect was accompanied with a marked increase in the membrane expression of beta-catenin, MUC18, plexins, integrins, and other proteins involved in cell adhesion and cancer metastasis. Taken together, our results show that Stat1/CD74 positive triple-negative tumors are more aggressive and suggest an approach for development of better diagnostics and more targeted therapies for triple negative breast cancer. This article is part of a Special Issue entitled: Proteomics: The clinical link.