MicroRNA-573 inhibits cell proliferation, migration and invasion and is downregulated by PICSAR in cutaneous squamous cell carcinoma
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The incidence of cutaneous squamous cell carcinoma (cSCC) has been increasing in recent years. Meanwhile, microRNAs (miRNAs) have been found to play vital roles in various cancers, including cSCC. This study aimed to investigate the expression of microRNA-573 (miR-573) in cSCC, its relationship with long non-coding RNA PICSAR and analyze its biological role. The relationship between PICSAR and miR-573 was confirmed by dual-luciferase reporter assay and Pearson’s correlation coefficient analysis. The levels of PICSAR and miR-573 were measured using quantitative Real-Time PCR. Cell Counting Kit-8 assay was used to evaluate the cSCC cell proliferation ability. The migration and invasion abilities of cSCC cells were evaluated by Transwell assay. PICSAR expression was increased and miR-573 was decreased in tumor tissues and cSCC cell lines. PICSAR and miR-573 can bind directly, and miR-573 expression was downregulated by PICSAR in cSCC. Overexpression of miR-573 significantly inhibited the proliferation, migration and invasion abilities of A431 and SCC13 cells. Additionally, miR-573 overexpression reversed the promotion effects of PICSAR overexpression on cSCC cell proliferation, migration and invasion abilities. In conclusion, our findings indicated that miR-573 expression was decreased in tumor tissues and cSCC cells and was downregulated by PICSAR in cSCC. Additionally, miR-573 overexpression inhibited cSCC cell proliferation, migration and invasion, and reversed the promotion effects of PICSAR overexpression on cSCC cell biological functions. Thus, miR-573 might function as a tumor suppressor and might be involved in the regulatory effects of PICSAR on tumorigenesis in cSCC.Keywords:
Tumor promotion
It is becoming increasingly evident that reactive oxygen species (ROS) act at different stages of carcinogenesis, and thus play multiple roles in oncogenesis. In addition to being mutagenic and initiating tumors, ROS or carcinogens that result in ROS generation may affect tumor promotion and progression through varied effects on growth promoting, growth inhibitory, or apoptotic signaling pathways.
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MicroRNA (miRNA) is an important type of non-coding RNAs with both physiological and pathological functions in human beings. Aberrant expression of miRNAs has been found in tumor tissues and the expression profile of certain groups of miRNAs is now emerging as bio-marker for cancer. It has been confirmed that miRNAs can exert oncogenic or tumor-suppressive functions through repressing the expression of their target genes which play different roles in tumorigenesis. The identification of oncogenic or tumor-suppressive miRNAs allows potential applications of these miRNAs as targets for cancer chemotherapy. In this review, we summarized the well-known cancer-related miRNAs reported in recent years and the roles they played in tumorigenesis and progression by targeting specific genes. Strategies developed to modulate the function or expression of the dysregulated miRNAs are also reviewed with recent examples illustrating their potential applications in cancer chemotherapy. Keywords: MicroRNA, oncogenic, tumor-suppressive, up-regulation, down-regulation, tumorigenesis, cancer chemotherapy.
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MicroRNA (miRNA ) 是在长度的 2123 核苷酸的小非编码的 RNA 分子的簇，它在 post-transcriptional 水平控制目标基因的表达式。最近的研究显示了 miRNA 在 carcinogenesis 起一个必要作用，例如影响房间生长，区别， apoptosis，和房间周期。现在，涉及 carcinogenesis 的 miRNA 的多重答应角色正在出现，并且 miRNA 仔细联系到 epithelialmesenchymal 转变(EMT ) 的进程，这被显示出，癌症干细胞(CSC ) 的规定，肿瘤侵略和移植的开发。miRNA 也充当稳定地在浆液表示的 biomarker 并且为各种各样的癌症的分子的目标治疗提供新目标。这评论的目的是在 carcinogenesis 说明 miRNA 的新角色并且在癌症加亮 miRNA 的新前景临床的申请，例如在血清学的诊断和分子目标的治疗学。
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Chemical carcinogenesis can be subdivided at least into two stages, i.e., initiation and promotion, in the mouse skin carcinogenesis model. There is considerable evidence supporting the relevance of the above concept to chemical carcinogenesis of other organs. Initiation represents the stage in which a carcinogen interacts with DNA and causes irreversible damage on the genome. Subsequent repeated exposure to a tumor promoter leads to a phenotypic expression of the initiated cells to tumor cells. In our living environment, a larger number of carcinogens may exist and exposure to a minute amount of carcinogen even once may be sufficient to generate initiated cells; therefore, prevention of carcinogenesis at the stage of initiation is not an easy task. In contrast to the initiation stage, the promotion stage is essentially reversible, and a relatively long period is required to accomplish this process. Therefore, prevention of chemical carcinogenesis in the promotion stage seems more practical than preventing carcinogenesis in the initiation stage. There is much evidence suggesting that arachidonic acid cascades play important roles both in the initiation stages. There is much evidence suggesting that arachidonic acid cascades play important roles both in the initiation and promotion stages. In the two-stage skin carcinogenesis, inhibitors of arachidonic acid cascades, especially lipoxygenase inhibitors, effectively prevent tumor formation by inhibiting the stage of tumor promotion caused by different types of tumor promoters. Although at present, the role(s) of lipoxygenase pathways in the mechanism of tumor promotion is not fully understood, the potential use of lipoxygenase inhibitors for the prevention of chemical carcinogenesis is anticipated.
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The multistage model of mouse skin tumorigenesis has been extremely useful for studying various factors that modify the carcinogenic process. Using this model system one can specifically study the effects of potential modifiers on both the initiation and the promotion stages independently. Studies have been performed on many exogenous compounds that have the capacity to inhibit (and in some cases enhance) the initiation phase by either: (i) alteration of the metabolism of the carcinogen (decreased activation and/or increased detoxification); (ii) scavenging of active molecular species of carcinogens to prevent their reaching critical target sites in the cells; (iii) competitive inhibition; or (iv) modulation of epidermal DNA synthesis. In addition, there have been a number of studies on compounds that either inhibit (or again in some cases enhance) promotion of skin carcinogenesis by (i) altering the state of differentiation; (ii) inhibiting the promoter-induced cellular proliferation; (iii) preventing gene activation by promoters; or (iv) scavenging free radicals and reactive oxygen species. Recent studies have also begun to unravel the nature of the tumor progression process of skin carcinogenesis. Many factors can modulate tumor progression including: (i) subsequent exposure to genotoxic agents; (ii) dose, duration and frequency of promoter treatment, (iii) chemical nature of the promoting agent. The multistage model of skin tumorigenesis has also begun to provide insight into the role of specific dietary, immunologic, and genetic factors involved in chemical carcinogenesis. It is believed that further study of all of these factors will greatly enhance our understanding of the process of chemical carcinogenesis in epithelial tissues in general as well as the process of skin carcinogenesis specifically. Finally, a greater understanding of those factors modifying skin tumorigenesis in mice will provide valuable information on the further development of early detection and prevention strategies for chemical carcinogenesis in humans.
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Both green and black tea have been shown to inhibit lung tumorigenesis in laboratory animal experiments. Green tea inhibited N-nitrosodiethylamine-induced lung tumor incidence and multiplicity in female A/J mice when tea was given either during the carcinogen treatment period or during the post-carcinogen treatment period. In a separate tumorigenesis model, both decaffeinated black tea and decaffeinated green tea inhibited 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor formation. Studies in which tea was administered during different time periods in relation to the NNK suggest that tea can inhibit lung tumorigenesis at both the initiation and promotion stages. The antiproliferative effects of tea may be responsible for these anti-carcinogenic actions. Black tea polyphenol preparations decreased NNK-induced hyperproliferation. Black tea also inhibited the progression of pulmonary adenomas to adenocarcinomas and the formation of spontaneous lung tumors in A/J mice. Growth inhibition by various tea polyphenols has been demonstrated in human lung H661 and H1299 cells. Although inhibition of cell growth and signal transduction pathways by tea components have been demonstrated, the concentrations required to produce the effect are higher than achievable in tissues in vivo. More research is necessary to translate these laboratory results to applications in human chemoprevention.
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The focus of this review is to provide state-of-the-art knowledge on the involvement of oxygen free radicals (OFR) in carcinogenesis with a particular reference to skin model system as the process of cancer development is best understood in this organ. However, a brief description of the role of OFR in other organs is also provided. The term OFR refers to forms of oxygen exhibiting high reactivity and having at least one unpaired electron. The role of OFR in different stages of carcinogenesis such as initiation, promotion and progression is described. Out of many mechanisms described for the chemical initiation of tumorigenesis, a number of them may involve free radicals in the cascade of reactions. Evidences that support the involvement of free radicals in tumor promotion include (i) a number of free radical-generating compounds are found to be tumor promoters in various animal model systems, (ii) ROS generating systems can mimic the biochemical action of tumor promoters, (iii) some tumor promoters stimulate the production of ROS, (iv) tumor promoters modulate the cellular antioxidant defense systems, and (v) free radical scavengers, detoxifiers and antioxidants inhibit the process of tumor promotion. The role of ROS in the progression stage of carcinogenesis is evident from the fact that a number of different free radical generating compounds enhance the malignant conversion of benign papillomas into carcinoma and their effectiveness may be related to the type of radicals produced into the biological system.
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The functional integrity of the intestinal epithelial barrier relies on tight coordination of cell proliferation and migration, with failure to regulate these processes resulting in disease. It is not known whether cell proliferation is sufficient to drive epithelial cell migration during homoeostatic turnover of the epithelium. Nor is it known precisely how villus cell migration is affected when proliferation is perturbed. Some reports suggest that proliferation and migration may not be related while other studies support a direct relationship. We used established cell-tracking methods based on thymine analog cell labeling and developed tailored mathematical models to quantify cell proliferation and migration under normal conditions and when proliferation is reduced and when it is temporarily halted. We found that epithelial cell migration velocities along the villi are coupled to cell proliferation rates within the crypts in all conditions. Furthermore, halting and resuming proliferation results in the synchronized response of cell migration on the villi. We conclude that cell proliferation within the crypt is the primary force that drives cell migration along the villus. This methodology can be applied to interrogate intestinal epithelial dynamics and characterize situations in which processes involved in cell turnover become uncoupled, including pharmacological treatments and disease models.—Parker, A., Maclaren, O. J., Fletcher, A. G., Muraro, D., Kreuzaler, P. A., Byrne, H. M., Maini, P. K., Watson, A. J. M., Pin, C. Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi. FASEB J. 31, 636–649 (2017). www.fasebj.org
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Abstract A new class of regulatory molecules known as microRNAs (miRNAs) is redefining our understanding of the molecular pathways associated with tumorigenesis. These miRNAs are small noncoding RNA (ncRNA) sequences with potent regulatory potential. The aberrant expression of miRNAs has been associated with the development of various tumors. It has been suggested that miRNAs can both regulate and act as tumor‐suppressor genes and oncogenes. Our understanding of the role of miRNAs in head and neck tumorigenesis is in its infancy. However, several recent studies have revealed extensive dysregulation of miRNA in head and neck tumors and have highlighted the potential of certain miRNAs to act as diagnostic and prognostic markers and targets for new therapeutic agents. The intent of this review is to discuss and summarize current findings that point to a significant role for miRNAs in head and neck tumorigenesis. © 2010 Wiley Periodicals, Inc. Head Neck, 2010
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