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。     

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。     

Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer

Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer.     

The role of microRNAs in the adrenocortical carcinomas

MicroRNAs (miRNAs) are a group of small, non-protein-coding RNAs that inhibit gene expressions through binding their 3′-UTR regions. Each miRNA can regulate a number of target genes and play crucial roles in a lot of biological processes including organogenesis, hematopoiesis, cell development, proliferation, and invasion. Deregulated expression of miRNAs has been found to be associated with initiation and development of tumors. Increasing evidences showed that miRNAs play a crucial role in adrenocortical carcinomas (ACCs). Aberrant miRNA expression may contribute to ACC carcinogenesis, and it can act as tumor-suppressive or oncogenic miRNAs. In this review, we reviewed the recent studies available on ACC-associated miRNAs. We try to summarize the contribution of miRNAs to the initiation and development of ACCs.     

Extracellular Vesicles As miRNA Nano-Shuttles: Dual Role in Tumor Progression

Tumor-derived extracellular vesicles (EVs) have a pleiotropic role in cancer, interacting with target cells of the tumor microenvironment, such as fibroblasts, immune and endothelial cells. EVs can modulate tumor progression, angiogenic switch, metastasis, and immune escape. These vesicles are nano-shuttles containing a wide spectrum of miRNAs that contribute to tumor progression. MiRNAs contained in extracellular vesicles (EV-miRNAs) are disseminated in the extracellular space and are able to influence the expression of target genes with either tumor suppressor or oncogenic functions, depending on both parental and target cells. Metastatic cancer cells can balance their oncogenic potential by expressing miRNAs with oncogenic function, whilst exporting miRNAs with tumor suppressor roles out of the cells. Importantly, treatment of cancer cells with specific natural and chemical compounds could induce the elimination of miRNAs with oncogenic function, thereby reducing their aggressiveness. In this review, we discuss the mechanisms by which EV-miRNAs, acting as miRNAs with oncogenic or tumor suppressor functions, could contribute to cancer progression.     

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

The aim of this study was to determine whether histone acetylation regulates tumor suppressive microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC) and to identify genes which are regulated by these miRNAs. We identified a miRNA that was highly upregulated in an ESCC cell line by cyclic hydroxamic acid-containing peptide 31 (CHAP31), one of the histone deacetylase inhibitors (HDACIs), using a miRNA array analysis. miR-375 was strongly upregulated by CHAP31 treatment in an ESCC cell line. The expression levels of the most upregulated miRNA, miR-375 were analyzed by quantitative real-time PCR in human ESCC specimens. The tumor suppressive function of miR-375 was revealed by restoration of miR-375 in ESCC cell lines. We performed a microarray analysis to identify target genes of miR-375. The mRNA and protein expression levels of these genes were verified in ESCC clinical specimens. LDHB and AEG-1/MTDH were detected as miR?375-targeted genes. The restoration of miR-375 suppressed the expression of LDHB and AEG-1/MTDH. The ESCC clinical specimens exhibited a high level of LDHB expression at both the mRNA and protein levels. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene. Knockdown of LDHB by RNAi showed a tumor suppressive function in the ESCC cells. The correlation between gene expression and clinicopathological features was investigated by immunohistochemistry for 94 cases of ESCC. The positive staining of LDHB correlated significantly with lymph node metastasis and tumor stage. It also had a tendency to be associated with a poor prognosis. Our results indicate that HDACIs upregulate miRNAs, at least some of which act as tumor suppressors. LDHB, which is regulated by the tumor suppressive miR-375, may therefore act as an oncogene in ESCC.     

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.     

Regulation of epithelial-mesenchymal transition through microRNAs: clinical and biological significance of microRNAs in breast cancer

Breast cancer is a malignant disease to treat among female worldwide due to its high capability to metastasize and mutate. Epithelial-mesenchymal transition is one of the essential processes involved in the metastatic capacity of breast cancer. In the recent time, the studies demonstrate that microRNAs, a kind of small non-coding RNA molecules, could be served as negative regulators in breast cancer, regulating cell cycle, drug resistance, and the process of metastasis in cancer development. With the assistance of microRNA profiling, the study concentrating on the regulatory function of miRNAs in breast cancer could be investigated more effectively and efficiently. More recent studies demonstrate that miRNAs have an important role to play in the EMT process of breast cancer to modulate metastasis. This small essay is on the purpose of demonstrating the significance and detection of miRNAs in breast cancer EMT process as oncogenes and tumor suppress genes through miRNA profiling according to the reports mainly in the recent 5 years, providing the evidence of efficient target therapy and effective pro-diagnosis focusing on miRNAs expression of breast cancer patients.     

microRNAs and lung cancer: tumors and 22-mers

Work over the last decade has revealed novel regulatory mechanisms in pathological disease states that are mediated by microRNAs and has inspired researchers to begin elucidating the specific roles of miRNAs in the regulation of genes involved in cancer development and progression. Recently, miRNAs have been explored as therapeutic targets and diagnostic markers of cancer. In this paper, we review recent advances in the study of miRNAs involved in tumorigenesis, focusing on miRNA regulation of genes that have been demonstrated to play critical roles in lung cancer development. We discuss miRNA regulation of genes that play critical roles in the process of malignant transformation, angiogenesis and tumor metastasis, the dysregulation of miRNA expression in cancer development, and the development of miRNA-based diagnostics and therapeutics.     

食管鳞状细胞癌中miRNAs的研究进展

食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）是我国常见食管癌（esophageal cancer, EC）的主要亚型。虽然ESCC从分子遗传学角度已被广泛研究,但其发病分子机制还没有完全阐明。microRNAs（miRNAs）是一类小的内源性非蛋白编码RNAs,在生理、病理过程中发挥着重要作用,包括细胞分化、凋亡、增殖和代谢。miRNAs通过致癌基因、抑癌基因在ESCC的发病机制中扮演着重要角色。近年来研究表明,许多miRNAs在ESCC组织中的表达存在明显的差异,了解miRNAs及其靶基因在ESCC发生发展中的作用,可能为早期检测、诊断、治疗和预后提供策略。     

Small molecule with big role: MicroRNAs in cancer metastatic microenvironments

Cancer metastasis is closely related to tumor cell microenvironments. Cancer cells and stromal cells interact with one another through extracellular matrix (ECM) and jointly participate in establishing the microenvironments. However, many questions remain to be addressed, in particular, a crucial question is which messengers mediate the mutual interaction and regulation between cancer cells and stromal cells. MicroRNAs (miRNAs), as oncogenic and oncosuppressor genes, regulate the expression and function of their related target genes to affect the biological behaviors of cancer cells and stromal cells, which may play an important role in cancer metastasis. Many miRNAs associated with cancer metastasis have been identified. The molecules of miRNAs are small and relatively easy to be secreted into extracellular microenvironments and devoured by nearby cells. As the regulatory messengers between cells, the secreted miRNAs function to regulate cancer cell proliferation, migration, intercellular communication and stromal modification, thereby helping cancer cells to establish their microenvironments for metastasis. In conclusion, miRNAs are small molecules, but they play a powerful role in regulating cancer metastatic ability by construction and modification of microenvironments.     

Pituitary tumor-transforming 1 increases cell motility and promotes lymph node metastasis in esophageal squamous cell carcinoma

Human pituitary tumor-transforming 1 (PTTG1)/securin is a putative oncoprotein that is overexpressed in various tumor types. However, the involvement of PTTG1 in gastrointestinal cancer development and progression remains unclear. In this study, we investigated the clinical significance and biological effects of PTTG1 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical studies performed on 113 primary ESCC specimens revealed a high prevalence of PTTG1 overexpression (60.2%), which was significantly associated with lymph node metastasis (regional, P = 0.042; distant, P = 0.005), advanced tumor stage (P = 0.028), and poorer overall survival (P = 0.017, log-rank test; P = 0.044, Cox proportional hazard model). Eleven ESCC cell lines expressed PTTG1 protein at levels 2.4 to 6.6 times higher than those in normal esophageal epithelial cells (HEEpiC). PTTG1 protein expression was confined to the nucleus in HEEpiC cells but present in both the cytoplasm and nucleus in ESCC cells. Two small interfering RNAs (siRNA) inhibited PTTG1 mRNA and protein expression in three ESCC cell lines by 77% to 97%. In addition, PTTG1 down-regulation by these siRNAs significantly reduced cell motility in all three ESCC cell lines (P < 0.01) in vitro, as well as popliteal lymph node metastases of ESCC cells in nude mice (P = 0.020). Global gene expression profiling suggested that several members of the Ras and Rho gene families, including RRAS, RHOG, ARHGAP1, and ARHGADIA, represented potential downstream genes in the PTTG1 pathway. Taken together, these findings suggest that PTTG1 overexpression promotes cell motility and lymph node metastasis in ESCC patients, leading to poorer survival. Thus, PTTG1 constitutes a potential biomarker and therapeutic target in ESCCs with lymph node metastases.     

Overexpression of cyclin B1 in human esophageal squamous cell carcinoma cells induces tumor cell invasive growth and metastasis

Cyclin B1, a key component in the control of cell cycle progression from G(2) to M phase, has been implicated in tumorigenesis and the development of malignancy. However, the underlying mechanism by which cyclin B1 acts as an important oncogenic molecule remains largely unknown. Here we show that ectopic expression of cyclin B1 promotes cell proliferation, enhances cell motility and migration and results in increased ability of cells extravasating through the capillary endothelium. Interestingly, isogenic esophageal squamous cell carcinoma (ESCC) cells overexpressing cyclin B1 reveal strong invasive growth and high potential of metastasis to lung in xenograft mice. Suppression of cyclin B1 expression via small interfering RNA approach in high-metastatic esophagus carcinoma cells specifically inhibits their ability to metastasize from the primary ESCC to lung. Notably, altered expression of epithelial markers and mesenchymal markers were observed in the cells overexpressing cyclin B1, suggesting that cyclin B1 contributes to metastasis probably by promoting an epithelial-mesenchymal transition. These results establish a mechanistic link between cyclin B1 and ESCC metastasis and provide novel insight into understanding of cyclin B1 in the development of ESCC malignancy.     

Metastamirs: a stepping stone towards improved cancer management

MicroRNAs (miRNAs) are non-coding RNAs that regulate protein expression. Aberrant miRNA expression in cancer has been well documented; miRNAs can act as oncogenes or tumor-suppressor genes, depending on the cellular context and target genes that they regulate, and are involved in tumor progression and metastasis. The potential mechanisms by which miRNAs are involved in tumor aggressiveness include migration, invasion, cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and apoptosis. MiRNAs are involved in various cellular pathways and an miRNA can elicit more than one biological effect in a given cell. Existing data show the potential clinical utility of miRNAs as prognostic and predictive markers for aggressive and metastatic cancers. The stability of miRNAs in formalin-fixed, paraffin-embedded tissues and body fluids is advantageous for biomarker discovery and validation. In addition, miRNAs can be extracted from small biopsy specimens, which is a further advantage. Finally, miRNAs are potential therapeutic agents for personalized cancer management.