The circular RNA NRIP1 plays oncogenic roles by targeting miR-505 through the activation of AMPK and PI3K/AKT/mTOR pathways in the renal carcinoma cell lines

doi:10.21203/rs.2.11445/v1

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The circular RNA NRIP1 plays oncogenic roles by targeting miR-505 through the activation of AMPK and PI3K/AKT/mTOR pathways in the renal carcinoma cell lines

https://doi.org/10.21203/rs.2.11445/v1

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Aims

To explore the roles and regulatory mechanisms of the circular RNA (circRNA) nuclear receptor-interacting protein 1 (NRIP1) (circNRIP1) in ACHN and CAKI-1 cells.

Methods

ACHN and CAKI-1 cells were transfected with si-circNRIP1 and microRNA-505 (miR-505) inhibitor or the corresponding controls. Cell viability was detected with the CCK-8. The protein expression levels of Bcl-2, Bax, cleaved-caspase-3, matrix metalloproteinase (MMP)-2, MMP-9, adenosine AMPK, AKT, PI3K, and mTOR were individually determined via western blot. qRT-PCR was used to examine the expressions of circNRIP1 and miR-505. The apoptotic rate, the colony numbers and the migration rate were separately determined by the annexin v-FITC/PI with flow cytometer, colony formation assay and modified two-chamber migration assay.

Results

circNRIP1 was overexpressed in tumor tissue. Silencing circZNF292 induced the inhibitions of cell viability, colony formation and migration, as well as the AMPK and PI3K/AKT/mTOR cascades but enhancement of apoptosis. si-circNRIP1 stimulated the up-regulation of miR-505, whose silence abolished the effects of si-circNRIP1 on these elements mentioned above.

Conclusion

The circNRIP1 played oncogenic roles by targeting miR-505 via stimulating AMPK and PI3K/AKT/mTOR cascades in the ACHN and the CAKI-1 cell lines.

Cancer Biology

Renal cell carcinoma

circNRIP1

miR-505

AMPK

PI3K/AKT/mTOR

Renal cell carcinoma (RCC), which is responsible for 3% of adult cancer incidences worldwide, is one of the most common tumors originated from renal tubular epithelial cells [1] with a high mortality rate [2]. However, the exact pathogenesis of renal carcinoma is not fully clear.

circRNAs are specific non-coding RNAs that are structurally characterized by a continuous closed loop, which is a key component that distinguishes from the circRNAs and linear RNAs [3]. Numerous evidences have indicated that circRNAs are capable of regulating genes expression at different transcription levels [4, 5]. This provided possibilities for circRNAs to get involved in the development of diseases. It has been found that the circRNAs play key roles in neurological disorders, diabetes and diverse cancers such as colorectal cancer, breast cancer and pancreatic ductal adenocarcinoma [6]. circ-hippocampus abundant transcript 1 (HIAT1) acted as a metastatic inhibitor to repress the migration and invasion processes in the AR-stimulated RCC cells [7]. What’s more, as a regulator of the miR-149-5p, circNRIP1 induced inhibitions of proliferation and migration, as well as the deactivation of AKT/mTOR cascade in gastric cancer (GC) cells [8]. This conclusion represented a compelling connection between the circNRIP1 and tumor development. Nevertheless, the functional mechanisms of circNRIP1 in RCC cell lines were needed to be investigated more detailed.

miRNAs are a class of endogenous short non-coding RNA molecules, found in eukaryotic cells, and regulate a variety of biological processes [9]. Abnormal expression of miR-505 has been observed in various cancers. Dang et al. found that miR-505 had some connection with GC cell proliferation and invasion [10]. Zhong et al. pointed out that miR-505 functioned as a tumor suppressor in RCC by down-regulating high mobility group box-1 protein (HMGB1) [11]. What’s interesting, circRNAs always exert dedicated regulatory functions in carcinoma via acting as a sponge of the miRNAs [12]. For instance, circRNA-100269 combined with miR-630 to adjust the proliferation of GC cells [13]. circ-PCNXL2 was extremely implicated in the proliferation and invasion of RCC cells by binding to miR-153 to modulate the expression of ZEB2 [14]. However, until nowadays, it has been incompletely investigated that how does the circNRIP1 function in RCC cells. The direct relationship between the circNRIP1 and the miR-505 was still undefined.

Here, the ACHN and CAKI-1 cell lines were considered as the experiment material. We screened for the underlying roles and mechanisms of the circNRIP1 in RCC in vitro.

Clinical specimens

The kidney cancer or the normal tissues were obtained from The Affiliated Hospital of Qingdao University Hospital (The Affiliated Hospital of Qingdao University, China). None therapies were administrated on the patients prior to the surgery. We obtained informed consents from all patients, and the present study was with the permission of the Medical Ethics Committee of the The Affiliated Hospital of Qingdao University Hospital.

Cell cultivation

The kidney cancer cells ACHN and CAKI-1 (ATCC, Manassas, Virginia, USA) were considered as the main study materials. The cells were cultured with RPMI-1640 (Gibco BRL, Grand Island, New York, USA) plus 10% fetal bovine serum (FBS, Gibco, Waltham, Massachusetts, USA), at 37°C with the humidity of 95% air and 5% CO₂, in line with the suggestions from ATCC.

Cell transfection

Small-interfering RNA (si)-circNRIP1 (si-circNRIP1) and miR-505 inhibitor as well as their corresponding negative controls (NC) (Life Technologies Corporation, Carlsbad, California, USA) were synthesized to alter the productions of the circNRIP1 and the miR-505 in ACHN and CAKI-1 cell lines. They were transfected into the cells via lipofectamine 3000 reagent (Invitrogen, Carlsbad, California, USA) for further experiment. Three days after transfection was selected as the optimum harvest time owing the highest transfection efficiency.

Cell viability assessing

The CCK-8 was introduced to detect cells viability in the present study. Firstly, different group cells were seeded into the 96-well plate with 5 × 10³ cells/well, and cultivated in a CO₂ incubator, for 24 h, at 37°C for further assays. Besides, referring to the instruction, the CCK-8 solution was injected and co-incubated with the cells for 1 h, after the 24 h conventional culture. Finally, the microplate reader (Bio-Rad, Hercules, California, USA) was introduced for absorbance measurement under 450 nm.

Colony formation assay

The 6-well plates, which contained 500 cells/well, were put into the carbon dioxide incubator and the cells were cultured for 2 weeks. After that, cells were fixed with paraformaldehyde (Sigma-Aldrich, St. Louis, Missouri, USA) and stained by crystal violet (Sigma-Aldrich). The colony formation ability was measured with a microscope (Olympus IX81, Tokyo, Japan).

Cell migration assay

A modified two-chamber migration assay (Millipore, Bedford, Massachusetts, USA) was conducted to test cells migration. The cells suspension were prepared with 200 μL serum-free medium (Gibco BRL) with a concentration of 5 × 10⁴ cells/ml. Followed by a two days conventional cultivation, the suspension was then injected in the upper chamber while 600 μL of serum-containing medium (Gibco BRL) was complemented into the lower chamber. After incubation, cells were rinsed 1-2 times with phosphate buffer saline (PBS), and the non-traversed cells were removed with a wet cotton swab. Moreover, the methanol (Beyotime Biotechnology, Shanghai, China) (20 min) and the crystal violet (Sigma-Aldrich) (10-20 min) were then individually used for cells handling. Finally, five fields were randomly selected for cell counting and photographing under the microscope (Canon, Tokyo, Japan).

Apoptosis assay

The cells apoptotic rate was measured by Annexin V-FITC/PI detection kit (Beijing Biosea Biotechnology, China) and the flow cytometer (Beckman Coulter, California, USA). Totally, these treated cells, which were adjusted and prepared in the 6-well plate with 1 × 10⁵ cells/well density and cultured at 37°C for 24 h, were washed and re-suspended with PBS. Annexin V-FITC and PI were mixed under 1:1, and co-incubated with the cell suspension in the dark for 15 min to constitute the sample for flow cytometer detecting.

Western blot

After cells collection, 1 × PBS buffer and 4°C RIPA buffer (Beyotime Biotechnology) containing protease inhibitors (Roche, Basel, Switzerland) was respectively used for total proteins extraction. The BCA™ Protein Assay Kit (Pierce, Appleton, Wisconsin, USA) was applied for protein quantification and the Bio-Rad Bis-Tris Gel system (Bio-Rad, Hercules, California, USA) was helped to form the western blot system. The primary antibodies were diluted with 5% blocking buffer, followed by the soak of polyvinylidene difluoride (PVDF) membrane (Millipore), which carried proteins blots at 4°C overnight. The primary antibodies were including anti-Bcl-2 (ab32124), anti-Bax (ab53154), anti-cleaved-caspase-3 (ab2302), anti-matrix metalloproteinase (MMP)-2 (ab92536), anti-MMP-9 (ab38898), anti-AMPK (ab131512), anti-p-AMPK (ab240058), anti-PI3K (ab40776), anti-p-PI3K (ab191606), anti-p-AKT (ab192623), anti-AKT (ab106693), anti-mTOR (ab32028), anti-p-mTOR (ab109268) and anti-β-actin (ab8227). Following 1 h attachment of horseradish peroxidase (HRP) signed secondary antibody, goat anti-rabbit (HRP) (ab7090) at 25°C, the PVDF membrane was put into the Bio-Rad ChemiDoc™ XRS system (Bio-Rad) with the addition of the Immobilon Western HRP Substrate (200 μL) (Millipore). Image Lab™ Software (Bio-Rad) was adopted to capture and quantify the protein bands.

Quantitative reverse transcription polymerase chain reaction (qRT-PCR)

Trizol reagent (Invitrogen, Carlsbad, California, USA) and the DNaseI (Promega, Madison, wisconsin, USA) were used for RNA extracting. The MultiscribeRTkit (Applied Biosystems) and random hexamers or oligo (dT) was consumed for the miRNA reverse transcription and qRT-PCR assessing. Experiment records were managed through 2^–^△△^Ct method and normalized with β-actin or U6.

Statistical analysis

The SPSS statistical software version 19.0 was the main tool for statistical analysis. The experimental data were showed as the mean + standard deviation (SD). Analysis of variance (ANOVA) or t-test was responsible for P values. P < 0.05 was considered to be statistically significant. All experiments in this study were repeated 3 times at least.

circNRIP1 is over-expressed in renal cancer tissue

The RNA expression level of circNRIP1 was detected through qRT-PCR. As was shown in our study, high expression of circNRIP1 was observed in the renal tumor tissues, in contrast with the control grouop (P < 0.001, Figure 1). This phenomenon showed that the circNRIP1 was closely related to renal cancer development.

Knockdown of circNRIP1 induces apoptosis and inhibitions of cell viability, colony formation and migration

In order to explore the functions of the circNRIP1 in ACHN and CAKI-1 cell lines, the si-circNRIP1 and si-NC were individually transfected into ACHN and CAKI-1 cell lines. Comparing with the corresponding group, si-circNRIP1 significantly led to a poor-expression of the circNRIP1 in both of the cells (both P < 0.001, Figure 2). It displayed that the si-circNRIP1 and si-NC were successfully constructed and transfected into cells. What’s more, the viability (both P < 0.05, Figure 3A) and the colony formation (P < 0.01 or P < 0.001, Figure 3B) of the ACHN and the CAKI-1 cells were notably restrained by the si-circNRIP1. However, the apoptotic rate (both P < 0.001, Figure 3C), and the productions of pro-apoptosis proteins such as Bax, cleaved-caspase 3 (all P < 0.001) were markedly increased by si-circNRIP1, which prevented the generation of the Bcl-2 on the contrary (both P < 0.001) (Figure 3D-3F). Meanwhile, the migration of the ACHN and CAKI-1 cells was detected as well. Generally, the migration rate (P < 0.05 or P < 0.01, Figure 3G), as well as the expressions of the MMP-2 (both P < 0.05) and MMP-9 (both P < 0.01) were evidently prevented by the si-circNRIP1 (Figure 3H-3J). All data indicated that circNRIP1 silence induced inhibitions of the proliferation, colony formation and migration, as well as the promotion of the apoptosis in both the ACHN and the CAKI-1 cells. circNRIP1 might be beneficial to the survival of the ACHN and the CAKI-1 cells.

circNRIP1 silence promotes the production of miR-505

To further study the potential mechanisms of the circNRIP1, we measured the expression level of the miR-505 relying on the qRT-PCR. In contrast with the relative group, the miR-505 was drastically up-modulated by the si-circNRIP1 (P < 0.001 or P < 0.01, Figure 4A). This outcome suggested that miR-505 was negatively controlled by the circNRIP1 in the ACHN and the CAKI-1 cells. Besides, the miR-505 inhibitor was successfully synthesized and transfected into the cell lines to restrain the miR-505 expression (both P < 0.001, Figure 4B), in contrast with the NC group.

circNRIP1 silence constrains cell viability, colony formation and cell migration but accelerates apoptosis via up-regulating miR-505

miR-505 inhibitor apparently elevated the cell viability (both P < 0.05, Figure 5A) and the colonies numbers (both P < 0.05, Figure 5B). The apoptotic rate (both P < 0.05, Figure 5C), and productions of apoptosis-related proteins (all P < 0.05), excluding the Bcl-2 (both P < 0.001) were down-regulated by the miR-505 inhibitor (Figure 5D-5F). Additionally, the migration rate (both P < 0.05, Figure 5G) of the ACHN and the CAKI-1 cells, as well as these migration-related proteins (all P < 0.05, Figure 5H-5J) were significantly increased by miR-505 inhibitor. These results demonstrated that the miR-505 inhibitor significantly abolished the effects of the si-circNRIP1 by promoting cell viability, colony formation and migration but preventing cell apoptosis. The miR-505, which was probably a target of the circNRIP1, was damage to the survival of the ACHN and the CAKI-1 cells.

circNRIP1 silence blocks AMPK and PI3K/AKT/mTOR signaling pathways by up-regulating miR-505

According to the western blot outcomes, the protein expression levels of the p-AMPK (Figure 6A) and the p/t-AMPK (P < 0.01 or P < 0.001) were notably decreased by the si-circNRIP1 in both of the ACHN and the CAKI-1 cells. Moreover, the influences of the si-circNRIP1 on the p-AMPK and the p/t-AMPK (both P < 0.001, Figure 6B) were disturbed by the miR-505 inhibitor. In addition, the protein expression levels of p-PI3K, p-AKT and p-mTOR (Figure 6D or Figure 6F) as well as the p/t-PI3K (P < 0.001 or P < 0.05), p/t-AKT (both P < 0.001) and p/t-mTOR (P < 0.01 or P < 0.05) were notably reduced by si-circNRIP1 in the ACHN and CAKI-1 cell lines. Likely, these phenomena were reversed by the miR-505 inhibitor, which mediated the increase of p-PI3K, p-AKT and p-mTOR, as well as the p/t-PI3K (P < 0.001 or P < 0.05), p/t-AKT (both P < 0.01) and p/t-mTOR (P < 0.05 or P < 0.01) (Figure 6E or Figure 6G). These data displayed that si-circNRIP1 deactivated the AMPK and PI3K/AKT/mTOR signaling cascades by promoting miR-505 in the ACHN and CAKI-1 cell lines. We could assume that circNRIP1 had the potential to trigger the signaling pathways by targeting miR-505.

We observed that the circNRIP1 was overexpressed in tumor tissues. Besides, the cell viability, the colony formation and migration were evidently reduced by si-circNRIP1 in both of the ACHN and CAKI-1 cell lines. On the contrary, the apoptosis was markedly promoted by si-circNRIP1. What’s more, circNRIP1 silence extremely induced the up-regulation of miR-505, and the effects of si-circNRIP1 were disturbed by the miR-505 inhibitor, showing a negative regulatory relationship between circNRIP1 and miR-505. Additionally, si-circNRIP1 deactivated the AMPK and PI3K/AKT/mTOR pathways, which was mediated via miR-505.

circRNAs are a type of non-coding RNA that have a stable closed-loop structure which make them hard to be decomposed by the enzymes [15]. A large number of evidences have indicated that circRNAs are closely related to the development of tumors [16]. For instance, circ-HIAT1 acted as a metastatic inhibitor to prevent androgen receptor (AR)-accelerated RCC cell migration and invasion by de-regulating miR-195-5p [7]. circ-ZNF609 was significantly overproduced in RCC cell lines, and thus promoted the cell proliferation and invasion through a novel network that was comprised by circ-ZNF609 and miR-138-5p [17]. What’s important, Zhang et al. demonstrated that circNRIP1 promoted tumor metastasis in vivo by inducing proliferation and migration as well as the activation of AKT/mTOR cascade in GC [8]. Similar outcomes were observed in our study that abnormal expression of circNRIP1 was associated with the tumorigenesis of renal carcinoma. circNRIP1 silence led to an inhibition of proliferation, colony formation and migration but promoted apoptosis in ACHN and CAKI-1 cell lines. This result exhibited a tumor promoting effect of the circNRIP1. Apoptosis and migration are typical features of cancer cells, while apoptosis is a unique morphological response to cellular stress [18]. The pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 are geared to the Bcl-2 family, which occupy important positions in the regulation of apoptosis [19, 20]. The migration ability is essential for development of cancer cells [21]. MMPs are the major secreted proteinases that are required for extracellular matrix (ECM) degradation to regulate tumor migration [22]. It is generally believed that changes in miRNAs expression have a significant correlation with the development of cancers [23]. For example, miRNA-7 acted as a tumor suppressor by targeting epidermal growth factor receptor (EGFR) [24]. miR-505 is known as a tumor suppressor and participated in the regulations of various cancers. miR-505 induces cell proliferation inhibition and apoptosis in breast cancer [25]. It was turned out by Chen et al. that miR-505 was overproduced in EC cells, leading to the reduction of TGF-α, MMP-2 and MMP-9, but enforced the productions of Bax and cleaved-PARP [26]. Additionally, Zhong et al. revealed that miR-505 functioned as a tumor suppressor in RCC by down-regulating HMGB1 [11]. Out of question, an ingenious phenomenon was obtained in this present investigation. The tumor inhibitory effect of miR-505 was completely eliminated by the miR-505 inhibitor, which resulted in an increase of cell viability, colony formation and migration, but a weak apoptosis. Besides, miR-505 inhibitor released the influences that derived from the si-circNRIP1, exhibiting a target relationship between the circNRIP1 and the miR-505. It could be concluded that circNRIP1 functioned in the ACHN and CAKI-1 cell lines by targeting the miR-505. Just like what was clarified by Zhang’s team that circNRIP1 functioned as a sponge of miRNA-149-5p to promote GC metastasis by inducing proliferation and migration as well as the AKT/mTOR cascade [8].

AMPK is the primary sensor and central regulator of cellular metabolism and energy status in mammalian tissues [27]. According to that, the AMPK pathway is capable of participating in the regulation of metabolic diseases or cancers [28, 29]. Generally, AMPK has potential capabilities cancers inhibition. Nonetheless, recent studies have shown that AMPK can play an oncogenic or anti-tumor effect in cancers depending on the specific situation [30, 31]. Brandon and colleagues found that AMPK activation could be conducive to the growth of tumor cells by modulating the metabolic plasticity and the flexibility [29]. What’s more, AMPK pathway was implicated in the functional effect of metformin in renal cancer [32]. Another investigation revealed that compound C modulated tumor apoptosis relying on AMPK pathway in human renal cancer cells [33]. In addition, PI3K/AKT/mTOR signaling pathway has direct connections with many cellular processes such as growth, motility and apoptosis [34]. Recent researches observed that PI3K/AKT/mTOR cascade is often irregular in various tumors, including breast cancer, colorectal cancer and RCC [35]. Xie et al. pointed out that awakening of PI3K/AKT/mTOR contributed to the cell invasion and poor prognosis in RCC tumors [36]. Besides, PI3K/AKT/mTOR signaling pathway, which led to an increase of proliferation and apoptosis reduction, had some connections with the inhibitory influences on RCC cell derived from the chlorogenic acid (CA) [37]. These conclusions indicated that the AMPK and the PI3K/AKT/mTOR signaling cascades occupied pivotal positions in RCC. We observed in our study that in the RCC cell lines ACHN and CAKI-1, knockdown of circNRIP1 blocked the AMPK and the PI3K/AKT/mTOR pathways by up-regulating miR-505. We could assume that si-circNRIP1 stimulated the miR-505 to exert anti-tumor effect through blocking the AMPK and the PI3K/AKT/mTOR pathways. The circNRIP1 is crucial for controlling pathway target expression in tumors, albeit a little available information, which is concerned about the direct regulation relationship between the circNRIP1 and these two signaling pathways, was accessed. Our achievement represented an undoubtly direct relationship between the circNRIP1, miR-505 and the AMPK and the PI3K/AKT/mTOR pathways. This result was partly confirmed by Zhang et al. who demonstrated that circNRIP1 promoted tumor metastasis by evoking the AKT/mTOR cascade in GC cells [8].

Above all, we found that the circNRIP1 might exhibit oncogenic roles by targeting miR-505 through the AMPK and the PI3K/AKT/mTOR pathways activation in the ACHN and the CAKI-1 cell lines.

circular RNA circRNA

nuclear receptor-interacting protein 1…..NRIP1

circular RNA nuclear receptor-interacting protein 1 circNRIP1

microRNA-505…..miR-505

matrix metalloproteinase …..MMP

Renal cell carcinoma …..RCC

circ-hippocampus abundant transcript 1…..HIAT1

gastric cancer…..GC

high mobility group box-1 protein…..HMGB1

Small-interfering RNA -circNRIP1…..si-circNRIP1

negative controls …..NC

phosphate buffer saline …..PBS

Quantitative reverse transcription polymerase chain reaction …..qRT-PCR

standard deviation…..SD

Analysis of variance …..ANOVA

extracellular matrix …..ECM

androgen receptor…..AR

epidermal growth factor receptor …..EGFR

chlorogenic acid …..CA

American Type Culture Collection ATCC

Ethics approval

We obtained informed consents from all patients, and the present study was with the permission of the Medical Ethics Committee of the The Affiliated Hospital of Qingdao University Hospital.

Consent for publication

Not applicable

Availability of data and material

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was funded by the Natural Science Foundation of Shandong Province (No.ZR2014HM059) and the Foundation of the Affiliated Hospital of Qingdao University (No.2018)

Authors' contributions

Conceived and designed the experiments: ZD and QHW; Performed the experiments and analyzed the data: HYW and JLJ; Contributed reagents/materials/analysis tools: TH and AK; Wrote and revised the manuscript: HN and YWC. All authors read and approved the final version of the manuscript and ensure this is the case.

Acknowledgements

Not applicable

Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA: a cancer journal for clinicians 2014, 64(1):9-29.
Shelar S, Shim EH, Brinkley GJ: Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer. 2018, 24(24):6433-6446.
Fischer JW, Leung AK: CircRNAs: a regulator of cellular stress. Critical reviews in biochemistry and molecular biology 2017, 52(2):220-233.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J: Natural RNA circles function as efficient microRNA sponges. Nature 2013, 495(7441):384-388.
Guo JU, Agarwal V, Guo H, Bartel DP: Expanded identification and characterization of mammalian circular RNAs. Genome biology 2014, 15(7):409.
Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, Mesteri I, Grunt TW, Zeillinger R, Pils D: Correlation of circular RNA abundance with proliferation--exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Scientific reports 2015, 5:8057.
Wang K, Sun Y, Tao W, Fei X, Chang C: Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer letters 2017, 394:1-12.
Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, Xu P, Sun G, Xu J, Lv J et al: Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. 2019, 18(1):20.
Pinzon N, Li B: microRNA target prediction programs predict many false positives. 2017, 27(2):234-245.
Dang SC, Wang F, Qian XB, Abdul M, Naseer QA, Jin W, Hu R, Gu Q, Gu M: MicroRNA-505 suppresses gastric cancer cell proliferation and invasion by directly targeting Polo-like kinase-1. OncoTargets and therapy 2019, 12:795-803.
Zhong B, Qin Z, Zhou H, Yang F, Wei K, Jiang X, Jia R: microRNA-505 negatively regulates HMGB1 to suppress cell proliferation in renal cell carcinoma. 2019.
Zhong Z, Lv M, Chen J: Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma. Scientific reports 2016, 6:30919.
Zhang Y, Liu H, Li W, Yu J, Li J, Shen Z, Ye G, Qi X, Li G: CircRNA_100269 is downregulated in gastric cancer and suppresses tumor cell growth by targeting miR-630. Aging 2017, 9(6):1585-1594.
Zhou B, Zheng P, Li Z: CircPCNXL2 sponges miR-153 to promote the proliferation and invasion of renal cancer cells through upregulating ZEB2. 2018, 17(23):2644-2654.
Li P, Chen S, Chen H, Mo X, Li T, Shao Y, Xiao B, Guo J: Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clinica chimica acta; international journal of clinical chemistry 2015, 444:132-136.
Zhang HD, Jiang LH, Sun DW, Hou JC, Ji ZL: CircRNA: a novel type of biomarker for cancer. Breast cancer (Tokyo, Japan) 2018, 25(1):1-7.
Xiong Y, Zhang J, Song C: CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138-5p in renal carcinoma. 2019, 234(7):10646-10654.
Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D'Orazi G: Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging 2016, 8(4):603-619.
Charununtakorn ST, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N: Potential Roles of Humanin on Apoptosis in the Heart. Cardiovascular therapeutics 2016, 34(2):107-114.
Li W, Jiang B, Cao X, Xie Y, Huang T: Protective effect of lycopene on fluoride-induced ameloblasts apoptosis and dental fluorosis through oxidative stress-mediated Caspase pathways. Chem Biol Interact 2017, 261:27-34.
Um E, Oh JM, Granick S, Cho YK: Cell migration in microengineered tumor environments. Lab on a chip 2017, 17(24):4171-4185.
Zhang JF, Wang P, Yan YJ, Li Y, Guan MW, Yu JJ, Wang XD: IL33 enhances glioma cell migration and invasion by upregulation of MMP2 and MMP9 via the ST2-NF-kappaB pathway. Oncology reports 2017, 38(4):2033-2042.
Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE: Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS genetics 2010, 6(12):e1001233.
Jiang L-h, Sun D-w, Li J, Tang J-h: MiR-139-5p: promising biomarker for cancer. Tumor Biology 2015, 36(3):1355-1365.
Yamamoto Y, Yoshioka Y, Minoura K, Takahashi RU, Takeshita F, Taya T, Horii R, Fukuoka Y, Kato T, Kosaka N et al: An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells. Molecular cancer 2011, 10:135.
Chen S, Sun KX, Liu BL, Zong ZH, Zhao Y: MicroRNA-505 functions as a tumor suppressor in endometrial cancer by targeting TGF-alpha. Molecular cancer 2016, 15:11.
Kim SM, Nguyen TT, Ravi A, Kubiniok P, Finicle BT, Jayashankar V, Malacrida L, Hou J, Robertson J, Gao D et al: PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells. Cancer Discov 2018, 8(7):866-883.
Zadra G, Batista JL, Loda M: Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies. Molecular cancer research : MCR 2015, 13(7):1059-1072.
Faubert B, Vincent EE, Poffenberger MC, Jones RG: The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer letters 2015, 356(2 Pt A):165-170.
Hardie DG: Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical cancer research : an official journal of the American Association for Cancer Research 2015, 21(17):3836-3840.
Yan M, Gingras MC, Dunlop EA, Nouet Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB et al: The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest 2014, 124(6):2640-2650.
Yang FQ, Wang JJ, Yan JS, Huang JH, Li W, Che JP, Wang GC, Liu M, Zheng JH: Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells. International journal of clinical and experimental medicine 2014, 7(10):3289-3296.
Jang JH, Lee TJ, Yang ES, Min do S, Kim YH, Kim SH, Choi YH, Park JW, Choi KS, Kwon TK: Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1. Experimental cell research 2010, 316(13):2194-2203.
Moritz A, Li Y, Guo A, Villen J, Wang Y, MacNeill J, Kornhauser J, Sprott K, Zhou J, Possemato A et al: Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Science signaling 2010, 3(136):ra64.
Husseinzadeh HD, Garcia JA: Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma. Current clinical pharmacology 2011, 6(3):214-221.
Xie J, Lin W, Huang L, Xu N, Xu A, Chen B, Watanabe M, Liu C, Huang P: Bufalin suppresses the proliferation and metastasis of renal cell carcinoma by inhibiting the PI3K/Akt/mTOR signaling pathway. Oncology letters 2018, 16(3):3867-3873.
Wang X, Liu J, Xie Z, Rao J, Xu G, Huang K, Li W, Yin Z: Chlorogenic acid inhibits proliferation and induces apoptosis in A498 human kidney cancer cells via inactivating PI3K/Akt/mTOR signalling pathway. The Journal of pharmacy and pharmacology 2019.

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The circular RNA NRIP1 plays oncogenic roles by targeting miR-505 through the activation of AMPK and PI3K/AKT/mTOR pathways in the renal carcinoma cell lines

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