Loss of hnRNPA2B1 inhibits malignant capability and promotes apoptosis via down-regulating Lin28B expression in ovarian cancer.
Yang Yu,Wei Qinglv,Tang Yuling,Yuanyuan Wang ,Luo Qingya,Zhao Hongyan,He Min,Wang Haocheng,Zeng Qi,Lu Weiliang,Xu Jing,Liu Tao,Yi Ping
Cancer letters
Ovarian cancer has the highest mortality rate among all gynecological cancers with its pathogenic mechanisms largely unknown. Here, we uncovered that ovarian cancer tissues exhibit higher heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) expression than normal ovarian epithelium tissues. Increased hnRNPA2B1 level matches along with poor prognosis of ovarian cancer patients. Importantly, hnRNPA2B1 inhibition hampers growth, reduces mobility of ovarian cancer cells in vitro and hinders xenograft tumor formation in vivo. Transcriptome profiling analysis reveals that hnRNPA2B1 dictates the expression of various important genes involved in tumorigenesis and Lin-28 Homolog B (Lin28B) is down-regulated upon hnRNPA2B1 loss. hnRNPA2B1 regulates expression of Lin28B via binding to Lin28B mRNA and enhancing its stability. Furthermore, knockdown of Lin28B reduces proliferation and mobility of ovarian cancer cells and impairs tumorigenesis in vivo, whereas Lin28B overexpression promotes xenograft tumor formation. Finally, re-expression of Lin28B in hnRNPA2B1 knockdown cells results in rescued phenotypes. Collectively, our results demonstrate that hnRNPA2B1 facilitates the malignant phenotype of ovarian cancer through activating Lin28B expression.
10.1016/j.canlet.2020.01.029
The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.
Liu Tao,Wei Qinglv,Jin Jing,Luo Qingya,Liu Yi,Yang Yu,Cheng Chunming,Li Lanfang,Pi Jingnan,Si Yanmin,Xiao Hualiang,Li Li,Rao Shuan,Wang Fang,Yu Jianhua,Yu Jia,Zou Dongling,Yi Ping
Nucleic acids research
N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its 'reader' YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.
10.1093/nar/gkaa048
Silencing the double-stranded RNA binding protein DGCR8 inhibits ovarian cancer cell proliferation, migration, and invasion.
Guo Yuqi,Tian Peng,Yang Chuanhe,Liang Zhibing,Li Min,Sims Michelle,Lu Lu,Zhang Zhan,Li Hongwei,Pfeffer Lawrence M,Yue Junming
Pharmaceutical research
PURPOSE:To evaluate the role of DiGeorge Critical Region 8 (DGCR8), a key component of miRNA biogenesis pathway in ovarian cancer. METHODS:The expression of DGCR8 in ovarian cancer was detected by immunostaining and DGCR8 knockdown in ovarian cancer cells was achieved using lentiviral shRNA. Differential expression of miRNAs was determined using Nanostring miRNA arrays and validated by real-time RT-PCR. RESULTS:DGCR8 was highly expressed in ovarian cancer. Knockdown of DGCR8 expression inhibits cell proliferation, migration, and invasion, as well as sensitizes cells to apoptosis induced by the chemotherapeutic drug cisplatin. Cellular survival pathways including ERK1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT were attenuated in DGCR8 knockdown cells. DGCR8 knockdown results in dysregulated miRNA gene expression. miR-27b was identified as the most highly down-regulated miRNA in DGCR8 knockdown cells and promoted cell proliferation in ovarian cancer cells. CONCLUSIONS:DGCR8 functions as an oncogene in ovarian cancer, which is in part mediated by miR-27b.
10.1007/s11095-013-1219-9
miR-1224-5p inhibits the proliferation and invasion of ovarian cancer via targeting SND1.
Wang Junrong,Hu Yubo,Ye Cong,Liu Junbao
Human cell
Emerging evidences have indicated that abnormal expression of microRNAs (miRNAs) contributed to carcinogenesis of ovarian cancer. However, the molecular mechanism of many aberrant expressed miRNAs was not known. Here, we discovered that miR-1224-5p was a downregulated miRNA in ovarian cancer via bioinformatic analysis and RT-qPCR. It was found that upregulation of miR-1224-5p inhibited cell proliferation and invasion ability of ovarian cancer cells. SND1, a well-characterized oncogene, was predicted as a target gene of miR-1224-5p. The western blotting, dual luciferase reporter assay, RNA-binding protein immunoprecipitation assay, and RT-qPCR demonstrated SND1 as a target gene of miR-1224-5p in ovarian cancer. MiR-1224-5p inhibited the expression of mesenchymal markers and increased the expression of epithelial markers in ovarian cancer cells via targeting SND1, indicating miR-1224-5p was involved in epithelial mesenchymal transition. The rescue assay manifested that miR-1224-5p-regulated cell proliferation and invasion mainly rely on downregulation of SND1 in ovarian cancer cells. In conclusion, our study revealed a direct regulatory association between miR-1224-5p and SND1 and their involvement in ovarian carcinogenesis.
10.1007/s13577-020-00364-4
Long noncoding RNA SNHG14 enhances migration and invasion of ovarian cancer by upregulating DGCR8.
Zhao J-L,Wang C-L,Liu Y-L,Zhang G-Y
European review for medical and pharmacological sciences
OBJECTIVE:Ovarian cancer is the most common fatal gynecologic malignancy in females all over the world. Recently, long noncoding RNAs (lncRNAs) have been reported to exert pivotal functions in tumorigenesis. In this research, lncRNA SNHG14 was studied to identify its role in the metastasis of ovarian cancer. PATIENTS AND METHODS:SNHG14 expression was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) in ovarian cancer specimens. Functional assays including wound healing assay, transwell assay, and Matrigel assay were performed to detect the effect of SNHG14 on the migration and invasion of ovarian cancer cells. In addition, the underlying mechanism was further explored through qRT-PCR and Western blot assay. RESULTS:SNHG14 level was dramatically higher in ovarian cancer specimens. Moreover, cell migration and invasion were significantly attenuated via the inhibition of SNHG14, while enhanced via the SNHG14 overexpression. Besides, the expression of DGCR8 mRNA and protein was markedly downregulated after the knockdown of SNHG14, while upregulated after SNHG14 overexpression. Furthermore, the expression level of DGCR8 was increased in cancer tissues and positively related to the expression of SNHG14 in ovarian cancer tissues. CONCLUSIONS:In summary, SNHG14 could enhance cell migration and invasion via upregulating DGCR8 in ovarian cancer.
10.26355/eurrev_201912_19659
Suppression of DDX39B sensitizes ovarian cancer cells to DNA-damaging chemotherapeutic agents via destabilizing BRCA1 mRNA.
Oncogene
Multiple RNA processing events including transcription, mRNA splicing, and export are delicately coordinated by the TREX complex. As one of the essential subunits, DDX39B couples the splicing and export machineries by recruiting ALYREF onto mRNA. In this study, we further explore the functions of DDX39B in handling damaged DNA, and unexpectedly find that DDX39B facilitates DNA repair by homologous recombination through upregulating BRCA1. Specifically, DDX39B binds to and stabilizes BRCA1 mRNA. DDX39B ensures ssDNA formation and RAD51 accumulation at DSB sites by maintaining BRCA1 levels. Without DDX39B being present, ovarian cancer cells exhibit hypersensitivity to DNA-damaging chemotherapeutic agents like platinum or PARPi. Moreover, DDX39B-deficient mice show embryonic lethality or developmental retardation, highly reminiscent of those lacking BRCA1. High DDX39B expression is correlated with worse survival in ovarian cancer patients. Thus, DDX39B suppression represents a rational approach for enhancing the efficacy of chemotherapy in BRCA1-proficient ovarian cancers.
10.1038/s41388-020-01482-x
Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.
Hsu K-F,Shen M-R,Huang Y-F,Cheng Y-M,Lin S-H,Chow N-H,Cheng S-W,Chou C-Y,Ho C-L
British journal of cancer
BACKGROUND:RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival. METHODS:Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used. RESULTS:From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients. CONCLUSION:Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.
10.1038/bjc.2015.254
The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.
Nucleic acids research
RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression of the protein in hepatocellular and lung cancers is correlated with adverse prognosis. LARP1 associates with an mRNA interactome that is enriched for oncogenic transcripts. Here we explore the role of LARP1 in epithelial ovarian cancer, a disease characterized by the rapid acquisition of resistance to chemotherapy through the induction of pro-survival signalling. We show, using ovarian cell lines and xenografts, that LARP1 is required for cancer cell survival and chemotherapy resistance. LARP1 promotes tumour formation in vivo and maintains cancer stem cell-like populations. Using transcriptomic analysis following LARP1 knockdown, cross-referenced against the LARP1 interactome, we identify BCL2 and BIK as LARP1 mRNA targets. We demonstrate that, through an interaction with the 3' untranslated regions (3' UTRs) of BCL2 and BIK, LARP1 stabilizes BCL2 but destabilizes BIK with the net effect of resisting apoptosis. Together, our data indicate that by differentially regulating the stability of a selection of mRNAs, LARP1 promotes ovarian cancer progression and chemotherapy resistance.
10.1093/nar/gkv1515