Regular paper

Circular RNA LPAR3 targets JPT1 via microRNA-513b-5p to facilitate glycolytic activation but repress prostate cancer radiosensitivity

Yuan Yuan Chen1, Li Ping Luo1 and Ke Chong Deng2

1Department of Oncology, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan City, Hubei Province, 430063, China; 2Department of Emergency, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan City, Hubei Province, 430063, China

A great many circular RNAs (circRNAs) are considered key modulators of human malignancies. However, the function of circRNA lysophosphatidic acid receptor 3 (LPAR3) in the radioresistance of prostate cancer (PCa) cells is still uncertain. circLPAR3, microRNA (miR)-329-3p, and JPT1 expression in PCa tissues and cells were detected by real-time quantitative PCR or western blot. Cell proliferation was detected by CCK-8 (cell proliferation assay) and colony formation assay, apoptosis was by flow cytometry, and migration and invasion ability were by Transwell assay. Cell glycolysis was analyzed by glucose uptake, lactate production, and ATP metabolism. Under different doses of radiation, the radiosensitivity of PCa cells was detected by colony formation assay. The relationship between circLPAR3, miR-513b-5p, and JPT1 was confirmed by dual luciferase reporter gene detection and RIP assay. The data presented that circLPAR3 and JPT1 expression was elevated in PCa, while miR-513b-5p expression was reduced. Repression of circLPAR3 depressed cell advancement, and restrained glycolysis, but enhanced the radiosensitivity of PCa cells. CircLPAR3’s target miRNA was miR-513b-5p which targeted JPT1. Elevated JPT1 reversed the repressive effects of circLPAR3 knockdown or miR-513b-5p overexpression on PCa advancement, glycolysis, and radiosensitivity. In summary, the knockdown of circLPAR3 reduces glycolysis, but promotes PCa radiosensitivity via the miR-513b-5p/JPT1 axis, discovering a novel mechanism in PCa progression.

Keywords: prostate cancer, circular RNA lysophosphatidic acid receptor 3, MicroRNA-513b-5p, Jupiter microtubule associated homolog 1, glycolysis, radiosensitivity

Received: 31 May, 2022; revised: 09 October, 2022; accepted:
29 January, 2023; available on-line: 17 March, 2023

e-mail: (LPL); (KCD)

Abbreviations: circRNA, circular RNA; JPT1, Jupiter microtubule associated homolog 1; LC, lung cancer; LPAR3, lysophosphatidic acid receptor; miRNAs, MicroRNAs; PCa, prostate cancer


Prostate cancer (PCa) is a common cancer among men worldwide, and its mortality rate ranks 2nd among men’s cancers (Wu et al., 2019). Recently, the incidence rate of PCa in China has manifested an upward trend (Zhou et al., 2021). In addition to surgical resection, radiotherapy is another treatment approach that can cure PCa (Li et al., 2020). Nevertheless, owing to radioresistance, the effectiveness of radiotherapy is unsatisfactory. Therefore, it is vital to explore a way to promote radiosensitivity.

Circular RNA (circRNA) is an endogenous non-coding RNA transcribed by RNA polymerase II, and featured by linking the 3’ with 5’ ends via exon or intron cycles (Kong et al., 2017). Studies have clarified that circRNA is crucial in various biological processes like apoptosis, cell vascularization, and cell invasion (Yuan et al., 2019). For instance, circRNA La-related RNA-binding protein 4 (LARP4) represses cell migration and invasion of PCa via targeting FOXO3A (Weng et al., 2020).. circRNA is differentially manifested in cancers and could serve as a latent modulator of tumorigenesis or cancer advancement. For instance, circ-membrane bound O-acyltransferase domain containing 2 accelerates PCa advancement via the miR-1271-5p/mTOR axis (Shi et al., 2020). CircRNA lysophosphatidic acid receptor 3 (LPAR3), a novel circRNA discovered recently, has been testified to be aberrantly manifested in several human cancers, like esophageal cancer (Shi et al., 2020) and ovarian cancer (Xu et al., 2020). However, its expression and function in PCa are not yet distinct.

MicroRNAs (miRNAs) are a set of short endogenous non-coding RNAs that could control approximately 30–50% of human protein-coding genes and molecular signaling pathways in cells (Porzycki et al., 2018). Accumulating evidence clarify that miRNAs are differentially expressed in cancers and impact cell growth, differentiation and apoptosis processes (Ghafouri-Fard et al., 2020). miRNA expression has become a latent biomarker for PCa diagnosis and prognosis (Nayak et al., 2020). For instance, miR-424/572 in recurrent PCa specimens are novel biomarkers for predicting PCa progression (Suer et al., 2019). MiR-215-5p reduces the metastasis of PCa via targeting phosphoglycerate kinase 1 (Chen et al., 2020). MiR-513b-5p is dysregulated in multiple human cancers, like lung cancer (LC) (Cai et al., 2020), hepatocellular carcinoma (Jin et al., 2021) and breast cancer (Lin et al., 2020). However, no research is presented to manifest what effects miR-513b-5p has on PCa.

In this study, we discovered the expression of circLPAR3 was more highly expressed in PCa samples than in controls. Therefore, we knock down circLPAR3 expression to identify its potential roles and explore possible mechanisms in carcinogenesis of PCa. Here, we demonstrated that circLPAR3 acted as a miR-513b-5p sponge to up-regulated Jupiter microtubule associated homolog 1 (JPT1). The research suggests that a novel circRNA may serve as a new biomarker for the early diagnosis and treatment of PCa.

Materials and Methods

Sample collection

Tumors and normal tissues adjacent to cancer were harvested from 58 patients with PCa in The Affiliated Hospital of Jiaxing University and stored in liquid nitrogen. Approval of this study was obtained from the Ethics Committee of The Affiliated Hospital of Jiaxing University and written informed consent was gained from each patient (Approval number: JX20156211).

Cell culture

PCa cell lines PC-3, LNCaP, VCaP, DU145 and human normal prostate epithelial cell line RWPE-1 were purchased from ATCC (MA, USA). PC3 cells were cultured in FK12 medium (Gibco, CA, USA), LNCaP cells were in RPMI-1640 medium (Gibco), VCaP cells were in 90% Dulbecco’s modified Eagle’s medium (Gibco), DU145 cells were in Eagle’s Minimum Essential Medium; and RWPE-1 cells were in Keratinocyte Serum-Free Medium Kit (Invitrogen, CA, USA). The mediums for PC cell culture were supplemented with 10% fetal bovine serum (Gibco).

Cell transfection

For the inhibition of circLPAR3 and JPT1, shRNA sequences targeting circLPAR3 and JPT1-specific siRNA (si-JPT1) sequences were synthesized by GenePharma. For miRNA overexpression, miR-513b-5p mimic was obtained from GenePharma. Gene overexpression vector (pcDNA-JPT1) and control vector (pcDNA) were purchased from Nanjing Jinrui Biotechnology Co., Ltd. After 24 h of cell culture, plasmids were transfected using Lipofectamine 3000 Transfection Reagent (Invitrogen).

RNase R treatment test

RNase R (6 units, Geneseed Biotech) was added to every 2 g RNA. After RNase R treatment, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to detect circLPAR3 and LPAR3 in LNCaP cells PMID: 34913472.

Actinomycin D test

The actinomycin D test was performed with LNCaP cells incubated with actinomycin D (2 mg/mL; Sigma-Aldrich, Tokyo, Japan) for 0, 4, 8, 12 and 24 h PMID: 34913472.

Cell counting kit (CCK-8) assay

About 3×103 cells were seeded in each well of a 96-well plate and detected proliferation at 24, 48 and 72 hours by CCK-8 (Dojindo, Haidian, Beijing, China). The absorbance at 450 nm was recorded at each time point, and the cell proliferation curve was drawn.

X-ray exposure

X-ray generator (Varian, Palo Alto, CA, USA) was applied to radiation management at a fixed rate of 4 Gy/min.

Colony formation and survival analysis

Approximately 140 transfected cells were incubated in each well of a 6-well plate for 14 to 21 days. Then the staining with 0.5% crystal violet (Yeasen) was observed under an inverted microscope (×40; Leica, Germany). For survival analysis, 200 cells were seeded on a 6-well plate and irradiated at 0, 2, 4, 6, and 8 Gy X-ray or not. Subsequently, a colony formation test was performed as described above.

Flow cytometry

Cells were treated with double-staining with fluorescein isothiocyanate-labeled annexin V (Invitrogen) and propidium iodide and then detected on a FACS Calibur flow cytometer (Becton Dickinson, San Jose, CA, USA) equipped with Cell Quest software (Becton, Franklin Lakes, NJ, USA) PMID: 31733095.

Migration and invasion test

A 24-well transwell chamber (Millipore, Billerica, MA, USA) with an 8 μm polycarbonate membrane was used to perform migration tests on LNCaP cells. Briefly, LNCaP cells (5×105 cells/well) were added into the upper chamber with 200 μL of serum-free medium, and the complete medium was added into the lower chamber as a chemoattractant. After 24 h, the migrating submembrane cells were fixed with 95% ethanol for staining with crystal violet (Beyotime, Shanghai, China) and imaging under the microscope (Leica). Image Lab software 5.2 (Bio-Rad, Hercules, CA, USA) was used for data analysis. The 24-well transwell was pre-covered with Matrigel (BD Biosciences) and was needed for invasion detection PMID: 31387394.

Glucose consumption, lactate production and adenosine triphosphate (ATP) levels

A glucose determination kit (Sigma), lactic acid colorimetric/fluorescence determination kit (BioVision) and CellTiter Glo Luminescent Cell survival Assay (Promega) were put to detect glucose consumption, lactate production and ATP levels (Zheng et al., 2020).


Total RNA was isolated from PC tissues and cells using TRIzol (Invitrogen). To measure miRNA expression, RNA was reverse transcribed into cDNA using the TaqMan miRNA Reverse Transcription Kit (Applied Biosystems) and then quantified by real-time PCR using TaqMan Universal PCR Master Mix and TaqMan RNA Detection (Applied Biosystems). To measure circRNA expression, RNA was reverse transcribed into cDNA using PrimeScript RT Reagent (Takara) and then quantified by SYBR Premix Ex Taq (Takara). U6 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were used as the internal reference. The 2-ΔΔCt method was put into use to calculate the relative miR-513b-5p and the target gene. RT-qPCR primer sequence was manifested in Table 1 PMID: 34515615.

Western blot analysis

Total protein was extracted from cell lysis buffer (Sangon Biotech), separated on 12% sulfate-polyacrylamide gel, and electroblotted onto a polyvinylidene fluoride membrane (Millipore, Billerica, MA, USA). Using primary antibodies JPT1 (ab126705; 1:1000; Abcam) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ab8245; 1:1000; Abcam), the membrane was incubated overnight. Added with the secondary antibody (1:2000, Promega), the membrane was analyzed by Odyssey Infrared Imaging System (LI-COR, Lincoln, NE, USA) PMID: 31624242.

The luciferase activity assay

Co-transfection of circLPAR3/JPT1-wild/mutant types (WT/MUT), miR-513b-5p mimic or miR-NC was conducted in LNCaP cells (Thermo Fisher Scientific) with Lipofectamine 3000. After 48 h, the relative activity of luciferase was detected via the dual Glo luciferase detection system (Promega, Shanghai, China).

RNA binding protein immunoprecipitation (RIP) assay

RNA immunoprecipitation kit (Millipore, Bedford, MA, USA) was carried out for RIP detection. LNCaP cells at a density of 5×105 cells/plate were treated with ice-cold radioimmunoprecipitation (RIPA) lysis buffer (Beyotime, Shanghai, China), incubated with protein A/G beads containing Anti-Argonaute 2 (anti-Ago2) or anti-Immunoglobulin G (anti-IgG). circLPAR3, miR-513b-5p and JPT1 were examined by RT-qPCR. N=3 (Du et al., 2020).

Statistical analysis

SPSS 21.0 (SPSS, Inc, Chicago, IL, USA) statistical software was applied to analyze the data. After the Kolmogorov-Smirnov test, the data were normally distributed and manifested as mean ± standard deviation (S.D.). The two-group comparison was conducted via t-test, while the comparison among multiple groups was via one-way analysis of variance (ANOVA), and Fisher’s least significant difference t-test (LSD-t). Enumeration data reported as rate or percentage were compared by chi-square test. P was a two-sided test; P<0.05 emphasized obvious statistical meaning.


We aimed to investigate circLPAR3 expression in PCa and its underlying molecular mechanism of regulating PCa progression by targeting JPT1 through miR-513b-5p. By collecting PCa clinical specimens and culturing PCa cells in vitro, we determined the relative expression levels of circLPAR3, miR-513b-5p and JPT1, and further verified their targeting relationship and interaction relationship. Our experiments found that circLPAR3 promoted glycolytic activation by targeting JPT1 through miR-513b-5p and inhibited PCa radiosensitivity. Therefore, our data are the first to investigate the function and mechanism of circLPAR3 in PCa, providing new insights into the pathogenesis of PCa.

Elevated circLPAR3 suggests an unpleasing into bad for PCa patients

CircRNAs are considered to be a promising marker for cancer diagnosis and prognosis. It has been reported that circLPAR3 promotes the migration, invasion and metastasis of esophageal cancer PMID: 32495982. However, the role of circLPAR3 in PCa is still unclear. We first explored the properties of circLPAR3: actinomycin D (Fig. 1A) and RNase R experiments (Fig. 1B) manifested that circLPAR3 was much larger than the linear transcript. circLPAR3 expression in PCa patient specimens was clearly elevated (Fig. 1C). In PCa cell lines, it was discovered that circLPAR3 in PCa cells was enhanced (Fig. 1D). Subsequently, we divided circLPAR3 into high expression and low expression according to the median expression level of circLPAR3 in clinical patients, and analyzed the clinicopathological characteristics of PCa patients, and found that circLPAR3 expression was associated with high Gleason score, advanced pathological T stage and distant metastases (Table 2). The survival analysis calculated by Kaplan Meier affirmed that PCa patients with elevated circLPAR3 had a lower survival rate than those with reduced circLPAR3 (Fig. 1E). All in all, the results affirmed that circLPAR3 suggested an unpleasing prognosis for PCa patients.

Silenced circLPAR3 weakens cell advancement and glycolysis, but enhances radiosensitivity

In order to immediately examine the functional role of circLPAR3 in PCa progression, the introduction of sh-circLPAR3 clearly reduced circLPAR3 (Fig. 2A). It was worth noting that knockdown of circLPAR3 repressed cell advancement (Fig. 2B–F). Glycolysis, characterized by enhanced glucose uptake and lactate accumulation, is a common feature of cancer cells PMID: 34237309. In the meantime, it was manifested that repressingcircLPAR3 restrained glucose uptake, lactate production and ATP levels (Fig. 2G–I). To improve the radiotherapy effect of PCa and improve the radiosensitivity, it is a hot research topic to understand the mechanism of cellular radioresistance PMID: 33033519. It was also determined whether circLPAR3 could impact the radiosensitivity of LNCaP cells in vitro. Moreover, with the application of sh-circLPAR3, the cell survival rate was clearly decreased after radiation exposure (Fig. 2J), revealing that circLPAR3 silencing enhanced cell radiosensitivity. The above data clarified silenced circLPAR3 weakened cell advancement with glycolysis but enhanced radiosensitivity in vitro.

CircLPAR3 absorbs miR-513b-5p in PCa cells

CircRNAs are involved in the regulation of miR sponges in PCa cells PMID: 34515615. Interestingly, the starBase database predicted a latent binding site between circLPAR3 and miR-513b-5p (Fig. 3A). For verifying whether circLPAR3 could adsorb miR-513b-5p, an experiment was implemented. It was discovered that miR-513b-5p mimic was available to reduce the luciferase activity of the circLPAR3-WT reporter plasmid, while had no clear effect on that of the MUT one (Fig. 3B). Then it was clarified that compared to the control IgG, circLPAR3 and miR-513b-5p were rich in microribonucleoprotein consisting of Ago2 (Fig. 3C). Moreover, reduced miR-513b-5p was detected in PCa (Fig. 3D, E) and was negatively linked with circLPAR3 expression in PCa samples (r=–0.637, Fig. 3F). In cells silencing circLPAR3, miR-513b-5p was found to be up-regulated (Fig. 3G). In general, circLPAR3 adsorbed miR-513b-5p and negatively modulated its levels in PCa cells.

MiR-513b-5p reduces PCa cell growth and glycolysis and promotes cellular radiosensitivity

Altered miRNA expression has been shown to play an important role in PCa invasion and metastasis PMID:34461437, while the expression of miR-513b-5p in PCa is unclear. It was confirmed that miR-513b-5p expression was elevated after miR-513b-5p mimic transfected into LNCaP cells (Fig. 4A). Subsequently, functional test data manifested that up-regulated miR-513b-5p repressed cell progression with glycolysis, but enhanced radiosensitivity in vitro (Fig. 4B–J). The above data confirmed that miR-513b-5p restrained growth and glycolysis, and promoted cellular radiosensitivity of PCa cells.

JPT1 is the immediate target of miR-513b-5p

As manifested in Fig. 5A, JPT1 was predicted to be miR-513b-5p’s target on StarBase. The miR-513b-5p-transfected JPT1 3’untranslated region (UTR)-WT group produced reduced luciferase activity. At the same time, for verifying whether the predicted binding site of JPT1 with miR-513b-5p was necessary for the two’s binding, mutation of the JPT1 binding site was conducted to construct the JPT1 3’UTR-MUT reporter plasmid. When co-transfection with miR-NC/513b-5p, the luciferase activity of the JPT1 3’UTR-MUT group was not impacted (Fig. 5B), suggesting that miR-513b-5p immediately interacted with JPT1. The other experiment also manifested miR-513b-5p was available to combine with JPT1 (Fig. 5C). JPT1 mRNA was clearly up-regulated in cancer tissues and PCa cells than normal tissues adjacent to cancer, and RWPE-1 cells (Fig. 5D, E). It was also discovered that JPT1 and miR-513b-5p were negatively linked (r = -0.616, Fig. 5F). In the meantime, in cells with up-regulated miR-513b-5p, it was found that JPT1 expression was suppressed (Fig. 5G). In summary, miR-513b-5p directly interacted with JPT1 in PCa cells.

Inhibition of JPT1 inhibits cell growth and glycolysis and promotes radiosensitivity in vitro

To further examine the functional role of JPT1 in PCa, we knocked down JPT1 in cells (Fig. 6A). Responded to inhibition of JPT1, cell growth and glycolysis were suppressed and radiosensitivity was induced (Fig. 6B–J). Collectively, inhibition of JPT1 inhibits cell growth and glycolysis, and promotes radiosensitivity in vitro.

Overexpression of JPT1 reversed the role of downregulated circLPAR3 or upregulated miR-513b-5p on cancer cell growth

For determining the influence of miR-513b-5p on PCa development and the possible mechanism, a rescue experiment was conducted by transfection with sh-circLPAR3 + pcDNA-NC, sh-circLPAR3 + JPT1, miR-513b-5p + pcDNA-NC or miR-513b-5p + JPT1 in LNCaP cells (Fig. 7A). The experiment clarified that elevated JPT1 reversed the repressive effects of silenced circLPAR3 or up-regulated miR-513b-5p on PCa advancement with glycolysis, and radiosensitivity (Fig. 7B–J). All in all, overexpression of JPT1 reversed the inhibition of circLPAR3 or upregulated miR-513b-5p on cancer cell growth.


At present, PCa has surpassed LC to become the most prevalent malignant tumor in American men. Although the overall survival rate of PCa patients has been improved owing to crucial advances in early screening and cancer management programs, the pathogenesis of PCa is still ambiguous yet (Wang et al., 2019). CircRNA has been proven to be a critical modulator of human cancer, and it can perform its functions via cooperating with its host gene (Liu et al., 2020). In this study, it was discovered for the first time that circLPAR3 was elevated in PCa patients, and PCa patients with upregulated circLPAR3 had a lower survival rate. This result suggested circLPAR3 could be applied as a latent biomarker for poor prognosis. Hence, exploring the function of circRNA in PCa can be a breakthrough to understand the pathogenesis of PCa.

A study has clarified that the reprogramming of cell metabolism is closely implicated in tumorigenesis and can be applied to cancer treatment (Xia et al., 2020). Because cancer cells have a strong ability to reproduce, hypoxia frequently shows up during tumor growth (Wang et al., 2019). As we all know, normal cells generally produce energy through mitochondrial oxidative phosphorylation, while quick cancer cell proliferation requires more energy. Therefore, the metabolic pathway of hypoxic cancer cells must be different from the normal metabolic pathway. It is reported that hypoxia facilitates the development of tumor cells to produce the inefficient pathways of ATP, making them inclined to gain energy via the glucose-dependent glycolysis pathway, which is necessary to maintain the rapid growth of tumors, also known as the Warburg effect (Dyshlovoy et al., 2020). Hence, repressing the activation of glycolysis is an effective treatment to prevent PCa. Numerous studies have clarified that circRNA is available to impact the glycolysis of cancer cells. For instance, circDENND4C accelerates the advancement with glycolysis of colorectal cancer cells via the miR-760/GLUT1 axis (Zhang et al., 2020). Circ_0057553/miR-515-5p controls PCa cell advancement with glycolysis via targeting YES1 (Zhang et al., 2020). In the meantime, in this study, it was discovered that circLPAR3 expression was also elevated in PCa cells. Knockdown of circLPAR3 clearly repressed cell advancement with glycolysis. Additionally, at the clinical level, radiation therapy is the most familiar and ideal cure way for PCa (Miszczyk et al., 2021). However, because cancer cells have different repair abilities after radiation, radioresistance has always been a challenge for cure (Ihara et al., 2019). It came out that the silencing of circLPAR3 clearly enhanced radiosensitivity.

Former studies have manifested that circRNA is available to be applied as a competitive endogenous RNA (ceRNA) of miRNA to adsorb miRNA to modulate mRNA gene expression (Shu et al., 2019). For instance, circ CCNB2 knockdown depresses autophagy of PCa cells via targeting the miR-30b-5p/KIF18A axis and makes PCa sensitive to radiation (Cai et al., 2020). In this study, it was confirmed that miR-513b-5p was a circLPAR3’s target. Former studies have testified that miR-513b-5p is crucial in various human cancers, like embryonic testicular cancer (Wang et al., 2017), breast cancer (Muti et al., 2018) and pancreatic cancer (Li et al., 2021). In the research, it was discovered the reduction of miR-513b-5p in PCa; Up-regulated miR-513b-5p repressed cell progression with glycolysis but enhanced radiosensitivity in vitro. As far as we know, this is the first study on miR-513b-5p in PCa.

Next, it was further figured out the downstream target genes of miR-513-5p. JPT1 is a protein-coding gene that impacts cell apoptosis and signal transduction (Bateman et al., 2020). A previous study has clarified that JPT1 is linked with the progression of PCa (Cheng et al., 2021). However, since there is very little research on JPT1, further studies are required to figure out the molecular mechanism of its action. In the research, it was discovered that JPT1 mRNA was clearly up-regulated in PCa. Moreover, elevated JPT1 reversed the effect of knocking down circLPAR3 or up-regulating miR-513b-5p on PCa cells, facilitating the advancement with glycolysis, but repressing radiosensitivity. All in all, JPT1 involves in circLPAR3/miR-513b-5p axis-regulated PCa cell growth and metastasis.

However, this research still has some limitations. First, owing to limited conditions, the sample size analyzed is limited. Secondly, in vivo animal experiments were not further conducted to verify the influence of the circLPAR3/miR-513b-5p/JPT1 axis on PCa in vivo. Finally, further exploration of the downstream target genes of JPT1 was not implemented. We hope that these issues can be further figured out in later studies.


In conclusion, the research has discovered a new mechanism of action of circRNA in PCa. It is found that circLPAR3 performs as a sponge of miR-513b-5p in PCa to restrain PCa cell glycolysis and accelerate radiosensitivity, while upregulation of JPT1 reverses this effect. The results indicate the circLPAR3/miR-513b-5p/JPT1 axis is supposed to be a latent prognostic and therapeutic target to improve the diagnosis and treatment of PCa.


Acknowledgments. Not applicable.

Declaration of Conflicting Interests. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.


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