Long noncoding RNA LOC646029 functions as a ceRNA to suppress ovarian cancer progression through the miR-627-3p/SPRED1 axis

doi:10.1007/s11684-023-1004-z

Front. Med.

2023, Vol. 17

Issue (5) : 924-938 https://doi.org/10.1007/s11684-023-1004-z

RESEARCH ARTICLE

Long noncoding RNA LOC646029 functions as a ceRNA to suppress ovarian cancer progression through the miR-627-3p/SPRED1 axis

Pengfei Zhao¹, Yating Wang², Xiao Yu¹, Yabing Nan¹, Shi Liu¹, Bin Li², Zhumei Cui³(

), Zhihua Liu¹(

)

¹. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
². Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
³. Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China

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Abstract

Long noncoding RNAs (lncRNAs) play a crucial regulatory role in the development and progression of multiple cancers. However, the potential mechanism by which lncRNAs affect the recurrence and metastasis of ovarian cancer remains unclear. In the current study, the lncRNA LOC646029 was markedly downregulated in metastatic ovarian tumors compared with primary tumors. Gain- and loss-of-function assays demonstrated that LOC646029 inhibits the proliferation, invasiveness, and metastasis of ovarian cancer cells in vivo and in vitro. Moreover, the downregulation of LOC646029 in metastatic ovarian tumors was strongly correlated with poor prognosis. Mechanistically, LOC646029 served as a miR-627-3p sponge to promote the expression of Sprouty-related EVH1 domain-containing protein 1, which is necessary for suppressing tumor metastasis and inhibiting KRAS signaling. Collectively, our results demonstrated that LOC646029 is involved in the progression and metastasis of ovarian cancer, which may be a potential prognostic biomarker.

Keywords ovarian cancer lncRNA LOC646029 metastasis microRNA 627-3p SPRED1

Corresponding Author(s): Zhumei Cui,Zhihua Liu

Just Accepted Date: 30 May 2023 Online First Date: 04 July 2023 Issue Date: 07 December 2023

Cite this article:

Pengfei Zhao,Yating Wang,Xiao Yu, et al. Long noncoding RNA LOC646029 functions as a ceRNA to suppress ovarian cancer progression through the miR-627-3p/SPRED1 axis[J]. Front. Med., 2023, 17(5): 924-938.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1004-z
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/924

Fig.1 LOC646029 was downregulated in ovarian cancer metastases and negatively correlated with ovarian cancer prognosis. (A) RNA-seq analysis revealed differentially expressed lncRNAs in 10 ovarian cancer samples, five primary samples, and five corresponding metastatic samples. (B) log₂ fold change of LOC646029 expression in 38 paired tissues (metastasis/primary). (C) Relative expression of LOC646029 in ovarian cancer cell lines was determined by RT-qPCR. (D) Representative images of LOC646029 expression in ovarian cancer tissues by ISH staining. (E) Overall survival of patients with ovarian cancer based on LOC646029 ISH analysis; n = 150. The results are shown as the mean ± SD of three independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig.2 LOC646029 functions as a tumor suppressor to inhibit ovarian cancer cell proliferation and metastasis in vitro and in vivo. (A, B) Relative cell viability of the indicated cell lines after LOC646029 overexpression or knockdown. (C, D) Transwell assays were performed to analyze the migration and invasion of 3AO and ES-2 cells after the overexpression of LOC646029. Scale bar = 500 μm. (E, F) Wound healing assays were performed to analyze the cell migration of 3AO and ES-2 cells after LOC646029 overexpression. Scale bar = 100 μm. (G) Representative images of macroscopic observations of metastatic lesions and range in nude mice. 3AO cells infected with lentivirus carrying LOC646029 or the corresponding empty vector was implanted into the peritoneal cavity of nude mice. (H) The number of metastatic nodules in the LOC646029 and empty vector groups (n = 6). (I) Representative images of xenograft tumors in the LOC646029 and empty vector groups (n = 6). (J) Tumor volumes were measured in the indicated groups (n = 6). The data are presented as the mean ± SD in (A–F) and the mean ± SEM in (H). * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig.3 MiR-627-3p is a direct target of LOC646029, which promotes ovarian cancer metastasis and proliferation. (A) Relative expression of the top 10 candidate miRNAs was detected by RT?qPCR after the overexpression of LOC646029. (B) Relative expression of miR-627-3p was detected by RT-qPCR after transfection with siRNA targeting LOC646029 or negative control. (C) Predicted matching sites between LOC646029 and miR-627-3p as well as the corresponding MUT form of the predicted binding site MUT. Relative luciferase activity was detected in A2780 and 293T cells cotransfected with LOC646029-WT or LOC646029-MUT and miR-627-3p mimics or NC-mimics. (D) Anti-Ago2 RIP assay was performed using A2780 cells followed by RT-qPCR to detect LOC646029 and miR-627-3p. (E) Relative expression levels of miR-627-3p in ovarian cancer cells were detected by RT-qPCR after transfection with miR-627-3p inhibitor or mimics. (F–H) Relative viability of A2780, TOV-21G, and 3AO cells after transfection with miR-627-3p inhibitor or mimics. (I–K) Representative images of Transwell invasion and migration assays and quantification of A2780 cells, TOV-21G and 3AO cells after transfection with miR-627-3p inhibitor or mimics. Scale bar = 500 μm. The data are presented as the mean ± SD of three independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig.4 SPRED1 is a crucial downstream target of miR-627-3p to suppress ovarian cancer cell proliferation, invasion, and migration. (A) Venn diagram showing the number of miR-627-3p target genes predicted by four bioinformatic databases. (B) Relative expression levels of candidate genes were determined by RT-qPCR after the knockdown of miR-627-3p. (C) Relative mRNA level and protein level of SPRED1 in A2780 and TOV-21G cells after transfection with miR-627-3p mimics or NC mimics. (D) Predicted binding sites between miR-627-3p and the 3′ UTR of SPRED1 and the corresponding mutant form in the miR-627-3p binding sites. Relative luciferase activity was detected in A2780 and 293T cells cotransfected with SPRED1-WT or SPRED1-MUT and miR-627-3p mimics or NC mimics. (E, F) Relative protein levels were detected in A2780 and TOV-21G cells transfected with NC-mimics, miR-627-3p mimics, and SPRED1 as indicated by Western blots. (G, H) Relative cell viability of A2780 and TOV-21G cells transfected with NC mimics, miR-627-3p mimics, and SPRED1 as indicated by the CCK8 assay. (I, J) Representative images of Transwell invasion and migration assays of A2780 and TOV-21G cells transfected with NC mimics, miR-627-3p mimics, and SPRED1 as indicated. The data are presented as the mean ± SD of three independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig.5 LOC646029 inhibits ovarian cancer progression by regulating miR-627-3p/SPRED1 signaling. (A, B) Relative mRNA and protein levels of SPRED1 in A2780 and 3AO cells after LOC646029 knockdown or overexpression, respectively. (C) Relative expression of SPRED1 and EMT markers was detected by RT-qPCR or Western blots in A2780 cells after the knockdown of LOC646029 and miR-627-3p as indicated. (D) Relative expression of SPRED1 and EMT markers was detected by RT-qPCR or Western blots in 3AO cells after the overexpression of LOC646029 and miR-627-3p as indicated. (E–G) CCK8 assay and Transwell assay analysis of A2780 cells transfected with negative control siRNA or siRNA targeting LOC646029 in the presence or absence of miR-627-3p inhibitor. (H–J) CCK8 assay and Transwell assay analysis of 3AO cells transfected with an empty vector or a vector expressing LOC646029 in the presence or absence of miR-627-3p mimics. (K) Relative expression level of SPRED1 in control or LOC646029-overexpressing tumor tissues by IHC staining. (L) Kaplan–Meier plotter was used to detect the overall survival of ovarian cancer patients with high and low SPRED1 expression. The data are presented as the mean ± SD of three independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig.6 LOC646029/miR-627-3p/SPRED1 axis suppresses the progression of ovarian cancer cells by the inhibition of Ras signaling. (A) Heatmap of RNA sequencing for differential gene expression profiles after the overexpression of LOC646029. (B) Top 15 signaling pathways negatively regulated by LOC646029 through KEGG pathway analysis. (C, D) The EMT and KRAS signaling pathway were negatively correlated with LOC646029; GSEA enrichment (C) and relative mRNA level (D) of selected genes from the process. (E–G) The protein levels of ERK, p-ERK, and SPRED1 in the indicated cells. The data are presented as the mean ± SD of three independent experiments. (H) Proposed model of the mechanism underlying the role of LOC646029 in the progression of ovarian cancer. * P < 0.05, ** P < 0.01, *** P < 0.001.

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