RNA-binding proteins in breast cancer: Biological implications and therapeutic opportunities.

RNA-binding proteins (RBPs) refer to a class of proteins that participate in alternative splicing, RNA stability, polyadenylation, localization and translation of RNAs, thus regulating gene expression in post-transcriptional manner. Dysregulation of RNA-RBP interaction contributes to various diseases, including cancer. In breast cancer, disorders in RBP expression and function influence the biological characteristics of tumor cells. Targeting RBPs has fostered the development of innovative therapies for breast cancer. However, the RBP-related mechanisms in breast cancer are not completely clear. In this review, we summarize the regulatory mechanisms of RBPs and their signaling crosstalk in breast cancer. Specifically, we emphasize the potential of certain RBPs as prognostic factors due to their effects on proliferation, invasion, apoptosis, and therapy resistance of breast cancer cells. Most importantly, we present a comprehensive overview of the latest RBP-related therapeutic strategies and novel therapeutic targets that have proven to be useful in the treatment of breast cancer.

[Retracted] Upregulation of miR­183­5p is responsible for the promotion of apoptosis and inhibition of the epithelial­mesenchymal transition, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin.

Following the publication of this article, a concerned reader drew to the Editor's attention that, in Fig. 9C on p. 2478 showing the results of Transwell invasion assay experiments, unexpected areas of similarity were identified in terms of the cellular patterns revealed both within the data panels for the six different experiments portrayed in this figure, and comparing among them. After having conducted an internal investigation, the Editor of International Journal of Molecular Medicine has reached the conclusion that the overlapping sections of data shown in this figure were unlikely to have arisen by coincidence. Therefore, on the grounds of a lack of confidence in the integrity of these data, the Editor has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused, and thanks the interested reader for drawing this matter to our attention. [International Journal of Molecular Medicine 42: 2469­2480, 2018; DOI: 10.3892/ijmm.2018.3853].

Beneficial effects of walnut (Juglans regia L.) oil-derived polyunsaturated fatty acid prevents a prooxidant status and hyperlipidemia in pregnant rats with diabetes.

BACKGROUND: Gestational diabetes mellitus has a long-term effect on pregnant women. Walnut (Juglans regia L.) oil-derived polyunsaturated fatty acid (PUFA) possesses multifarious pharmacological activities. This study investigated the beneficial effects of walnut oil-derived PUFA on glucose metabolism, pregnancy outcomes, oxidative stress, and lipid metabolism in gestational diabetes mellitus. METHODS: The GDM rat model was generated by intraperitoneal injection of streptozotocin (40 mg/kg) on gestational day (GD) 6, GD7 and GD8. The differences between groups were estimated using one-way ANOVA followed by the Tukey's multiple comparison test for post-hoc analysis. RESULTS: The results indicated that PUFA could mitigate GDM in pregnant diabetic rats, as embodied by the decrease of fasting blood glucose and the increase of plasma insulin and hepatic glycogen levels. Also, PUFA could suppress oxidative stress in pregnant diabetic rats, as reflected by the decrease of malondialdehyde content, an increase of superoxide dismutase, catalase and gutathione peroxidase activities. PUFA could also mitigate the abnormal changes of lipid profiles in plasma and hepatic tissue. Moreover, the relative mRNA expression of sterol regulatory element-binding transcription factor-1, stearoyl-CoA desaturase-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, was suppressed by PUFA in pregnant diabetic rats. CONCLUSIONS: These results suggested that PUFA supplementation during pregnancy is beneficial in preventing diabetic complications in pregnant rats.

Circular RNA-ITCH Inhibits the Proliferation of Ovarian Carcinoma by Downregulating lncRNA HULC.

Circular RNA-ITCH has been proven to be tumor suppressor in esophageal and lung cancer, while the role of this RNA in other types of cancers is unknown. In this study, we observed that circular RNA-ITCH was downregulated, while lncRNA HULC was upregulated in ovarian carcinoma. Circular RNA-ITCH and HULC were inversely and significantly correlated. Overexpression of circular RNA-ITCH resulted in inhibited, while overexpression of HULC promoted the proliferation of cells of ovarian cancer cell lines. Overexpression of circular RNA-ITCH led to inhibited HULC in cells of ovarian cancer cell lines, while overexpression of HULC failed to significantly affect the expression of circular RNA-ITCH but attenuated the inhibitory effects of circular RNA-ITCH overexpression. However, overexpression of circular RNA-ITCH failed to affect cancer cell behaviors. Therefore, circular RNA-ITCH may inhibit the proliferation of ovarian carcinoma by downregulating HULC.

The proliferation of cervical cancer is promoted by miRNA-125b through the regulation of the HMGA1.

BACKGROUND: It has been reported that miRNA-125b is associated with carcinogenesis and development of several different kinds of cancers. Nevertheless, there is no clarity regarding the significance and mechanism of action of miR-125b in clinical practice for cervical cancer (CC). MATERIALS AND METHODS: In the current investigation, the expression of miR-125b in cervical clinical specimens and CC cell lines was analyzed via real-time quantitative PCR, and the relationship of miR-125b with the chromatin-associated protein high mobility group A (HMGA1) expression and clinicopathological parameters of CC patients was explored. RESULTS: The results indicated that miR-125b expression was remarkably upregulated in CC cell lines as well as in the tissues of humans. miR-125b overexpression was significantly related to a decrease in HMGA1 expression, progression-free survival, overall survival, and prognosis as well. Besides, knockdown of miR-125b inhibited proliferation and colony formation in SW756 and C4-1 cells, where the 3'-UTR of HMGA1 mRNA was directly targeted. Moreover, PI3K/Akt pathway was regulated by miR-125b through suppression of HMGA1. CONCLUSION: These findings illustrated that a new regulatory role of HMGA1 is involved in the progression of CC. Our data demonstrated that miR-125b could play a critical role in the carcinogenesis and progression of CC, revealing that miR-125b might serve as a potential new target for treating CC.

Up-regulation of miRNA-148a inhibits proliferation, invasion, and migration while promoting apoptosis of cervical cancer cells by down-regulating RRS1.

The purpose of the present study is to figure out the role of miRNA-148a (miR-148a) in growth, apoptosis, invasion, and migration of cervical cancer cells by binding to regulator of ribosome synthesis 1 (RRS1). Cervical cancer and adjacent normal tissues, as well as cervical cancer cell line Caski, HeLa, C-33A, and normal cervical epithelial cell line H8 were obtained to detect the expression of miR-148a and RRS1. Relationship between miR-148a and RRS1 expression with clinicopathological characteristics was assessed. The selected Caski and HeLa cells were then transfected with miR-148a mimics, miR-148a inhibitors or RRS1 siRNA to investigate the role of miR-148a and RRS1 on proliferation, apoptosis, colony formation, invasion, and migration abilities of cervical cancer cells. Bioinformatics information and dual luciferase reporter gene assay was for used to detect the targetting relationship between miR-148a and RRS1. Down-regulated miR-148a and up-regulated RRS1 were found in cervical cancer tissues and cells. Down-regulated miR-148a and up-regulated RRS1 are closely related with prognostic factors of cervical cancer. RRS1 was determined as a target gene of miR-148a and miR-148a inhibited RRS1 expression in cervical cancer cells. Up-regulation of miR-148a inhibited cell proliferation, migration, and invasion while promoting apoptosis in Caski and HeLa cells. Our study suggests that miR-148a down-regulates RRS1 expression, thereby inhibiting the proliferation, migration, and invasion while promoting cell apoptosis of cervical cancer cells.

Decreased expression of long non-coding RNA SNHG7 cause recurrent spontaneous abortion through suppression proliferation and invasion of trophoblast cells via miR-34a.

Little is known about the role of long non-coding RNA SNHG7-1 in the development of recurrent spontaneous abortion (RSA). The aim of the present study was to investigate the levels of SNHG7-1 in villi of RSA, and explore its underlying mechanism. The qRT-PCR assay SNHG7-1 showed that the expression level was downregulated in RSA and HTR-8/SVneo cells. In addition, the growth rate of cells transfected with si-SNHG7-1 was significantly decreased compared to that with si-NC, which was reversed by miR-34a targeted with 3'-UTR. Moreover, miR-34a suppressed the expression of WNT1 by binding with the 3'-UTR, which interact with WNT1 to inhibit the proliferation of cells. Furthermore, miR-34a inhibitor rescued the dysregulation of WNT1, p-ß-catenin, ß-catenin, cyclinD and c-Myc by si-SNHG7A-1. In short, the current study suggests SNHG7-1 plays as an important role in RSA progression targeted by miR-34a via Wnt/ß-catenin signaling pathway, providing a novel insight for the pathogenesis and underlying therapeutic target for RSA.

KDM5A Regulates a Translational Program that Controls p53 Protein Expression.

The p53 tumor suppressor pathway is frequently inactivated in human cancers. However, there are some cancer types without commonly recognized alterations in p53 signaling. Here we report that histone demethylase KDM5A is involved in the regulation of p53 activity. KDM5A is significantly amplified in multiple types of cancers, an event that tends to be mutually exclusive to p53 mutation. We show that KDM5A acts as a negative regulator of p53 signaling through inhibition of p53 translation via suppression of a subgroup of eukaryotic translation initiation genes. Genetic deletion of KDM5A results in upregulation of p53 in multiple lineages of cancer cells and inhibits tumor growth in a p53-dependent manner. In addition, we have identified a regulatory loop between p53, miR-34, and KDM5A, whereby the induction of miR-34 leads to suppression of KDM5A. Thus, our findings reveal a mechanism by which KDM5A inhibits p53 translation to modulate cancer progression.

Upregulation of miR-183-5p is responsible for the promotion of apoptosis and inhibition of the epithelial-mesenchymal transition, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin.

Endometrial cancer is a life­threatening malignancy that affects women all over the world, and it has an increasing incidence. MicroRNAs (miRNAs/miRs) have been reported to be involved in cellular activities in endometrial cancer. The present study aimed to examine the effects of miR­183­5p on the epithelial­mesenchymal transition (EMT), proliferation, invasion, migration and apoptosis of human endometrial cancer cells by targeting Ezrin. Primary endometrial cancer tissues and adjacent normal tissues were obtained for the investigation. The protein expression of Ezrin in tissues was detected by immunohistochemistry. The expression level of miR­183­5p and the mRNA and protein expression levels of Ezrin and EMT­associated genes were determined by reverse transcription­quantitative polymerase chain reaction and western blot analyses. Endometrial cancer cells were treated with miR­183­5p inhibitors, small interfering RNA targeting Ezrin or miR­183­5p inhibitors. Cell proliferation, cell cycle, apoptosis, migration and invasion were then evaluated using an MTT assay, flow cytometry, scratch test and Transwell assay, respectively. Compared with normal adjacent tissues, the expression of miR­183­5p was decreased in endometrial cancer tissues, and the expression of Ezrin was significantly increased in endometrial cancer tissues. The protein expression of Ezrin was correlated with the severity and poor prognosis of endometrial cancer. Notably, the target prediction program and the luciferase reporter gene assay confirmed that miR­183­5p targeted and negatively regulated the expression of Ezrin. In vivo experiments revealed that the increased expression of miR­183­5p and decreased expression of Ezrin inhibited EMT, cell proliferation, migration and invasion, but promoted cell apoptosis in Ishikawa cells. These results suggested that the upregulated expression of miR­183­5p promoted apoptosis and suppressed the EMT, proliferation, invasion and migration of human endometrial cancer cells by downregulating Ezrin.