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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 2  |  Page : 317-323

Receptors for advanced glycation end products is associated with autophagy in the clear cell renal cell carcinoma


1 Department of Urology, Shanghai Tenth People's Hospital of Nanjing Medical University, Nanjing; Transplantation Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
2 Department of Pathology, The Fifth Hospital of Shijiazhuang, Shijiazhuang, China
3 Department of Urology, Shanghai Tenth People's Hospital of Nanjing Medical University, Nanjing, China
4 Department of Urology, Shanghai General Hospital of Nanjing Medical University, Nanjing; Department of Urology, The Affiliated First People's Hospital of Shanghai Jiao Tong University, Shanghai, China

Date of Web Publication1-Apr-2019

Correspondence Address:
Dr. Jun-Hua Zheng
No. 101, Longmin Street, Nanjing Medical University, Jiangning, Nanjing 211166
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_180_18

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 > Abstract 


Background: The receptor for advanced glycation end-product (RAGE) was one of the signal transduction receptors. RAGE interacted with various signaling molecules which were involved in human disease processes including tumorigenesis. Previous reports have indicated that RAGE/high-mobility group box 1 (HMGB1) could regulate autophagy in different carcinomas. However, the functional role of RAGE/ HMGB1 in the regulation of clear cell renal cell carcinoma (ccRCC) autophagy remained unrevealed.
Methods: Western blot, quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence were used in the present study.
Results: In this study, we demonstrated that the levels of RAGE/HMGB1 and autophagic protein LC3, Beclin-1, PI3K were much higher in ccRCC samples than those of in adjacent normal tissues. RAGE and autophagic protein expression was regulated with RAGE/HMGB1 in human RCC cell lines.
Conclusion: Our results implicated that RAGE and autophagy played important roles in ccRCC, and RAGE/HMGB1 might serve as a novel therapeutic target for future ccRCC treatment.

Keywords: Autophagy, clear cell renal cell carcinoma, high-mobility group box 1, receptor for advanced glycation end-product


How to cite this article:
Guo Y, Zhang HC, Xue S, Zheng JH. Receptors for advanced glycation end products is associated with autophagy in the clear cell renal cell carcinoma. J Can Res Ther 2019;15:317-23

How to cite this URL:
Guo Y, Zhang HC, Xue S, Zheng JH. Receptors for advanced glycation end products is associated with autophagy in the clear cell renal cell carcinoma. J Can Res Ther [serial online] 2019 [cited 2019 Nov 18];15:317-23. Available from: http://www.cancerjournal.net/text.asp?2019/15/2/317/255085




 > Introduction Top


The kidney is composed of heterogeneous populations of cells. These cells cooperate together and take part in a variety of complex and interdependent processes. Many studies have demonstrated that kidney diseases had a potential association with inflammation.[1] Renal cell carcinoma (RCC) was a common urologic cancer. In 2014, it accounted for about 2%–3% of all malignancy cases in global adults.[2] Moreover, the incidence of RCC has steadily increased in recent years.[2] The surgical resection of RCC led to a 5-year survival of nearly 90%.[3] Clear cell RCC (ccRCC) was one of the most common histological types of RCC, which accounted for about 70%–80% of the RCC.[4] However, the exact cause and mechanism of the ccRCC development remained unrevealed. Therefore, it is urgent to investigate the pathogenesis of ccRCC in detail for better prevention and treatment. Recently, growing evidence demonstrated that tumor microenvironment (TME) contributed a lot to the progression of malignancy.

The receptor for advanced glycation end-product (RAGE) is one of the signal transduction receptors which interact with various downstream signaling molecules, including high-mobility group box 1 (HMGB1), S100/calgranulins, β-amyloid, AGEs, phosphatidylserine, C3a, and advanced oxidation protein products.[5] RAGE has been reported to participate in a variety of human disease processes, such as diabetes, cardiovascular diseases, and cancers.[6] The expression of RAGE is very low or even few in normal tissues. Nevertheless, the RAGE expression would be enhanced in cancer and chronic inflammation, enabled it a perfect predictor in the progression and prognosis of physical disorders, such as chronic inflammation and diabetic complications. However, until now, the precise contributions of RAGE in renal cancer remained unrevealed. Growing evidence demonstrated that RAGE was involved in the progression of various human cancers, including RCC, pancreatic cancer, prostate cancer, colon cancer, esophageal cancer, biliary cancer, gastric cancer, and lung cancer.[7],[8],[9],[10],[11] Furthermore, the suppression of RAGE signaling has been applied to inhibit tumor proliferation, migration, and angiogenesis in various cancers.[12],[13],[14],[15] Therefore, there is growing interest and urgent need to elucidate the intracellular pathways through which RAGE participated in these disease-related processes. RAGE was known to interact with a variety of signaling molecules.[16] Earlier reports generally focused on inflammatory-associated pathways, such as the nuclear factor-kappa B (NFκB)[17] and the mitogen-activated protein kinase (MAPK)[18] signaling. Recently, it also confirmed that many innovative pathways would be activated on the stimulation of RAGE. One of these pathways was involved in autophagy, which devoted to the final effects of RAGE.

HMGB1 is a nuclear DNA binding protein which has been discovered more than 30 years ago.[19] It was demonstrated to function as a potent proinflammatory cytokine. HMGB1 plays its roles through several cell-surface receptors including the toll-like receptors (TLRs) and RAGE. Studies have indicated that HMGB1 played critical roles in the pathogenesis of RCC and multiple kidney diseases.[7]

Autophagy is a conserved process, in which cytoplasmic material is degraded by lysosomes or vacuoles and then recycled. It contributed to the recycling of metabolic substances and make effects on maintaining cellular homeostasis.[20] Recent reports suggested that autophagy was a key factor for regulating cancer cell survival in human cancers. It allowed cells to survive in the hypoxic and nutrient-deprived TME.[21] Therefore, RAGE-mediated autophagy may play critical roles in TME.

In this study, we demonstrated the relationship between HMGB1/RAGE and autophagy in ccRCC. We investigated the expression levels of HMGB1/RAGE, LC3, Beclin-1, and PI3K in ccRCC samples and adjacent normal tissues. The dysregulation of HMGB1/RAGE was found to be one of the major mechanisms leading to the autophagy in ccRCC. Our results presented novel insights into understanding the molecular mechanism of autophagy in ccRCC, which provided a future direction of interventional therapy for ccRCC.


 > Materials and Methods Top


Ethics statement

This research was reviewed and approved by the Ethics Committee of the first affiliated hospital of Wenzhou Medical University. The informed consents were obtained from all the patients. The whole procedure including specimen collection was harmless. The whole research conformed to the principles in the Declaration of Helsinki.

Primary tumors

From January 2016 to July 2016, RCC tissues and paired adjacent nontumorous renal tissues (≥3 cm away from the tumor, confirming that no cancer cell was found in the tangent lines) were obtained from 12 patients with RCC, who received tumor nephrectomy at first affiliated hospital of Wenzhou Medical University. All specimens from nephrectomy were immediately snap-frozen in liquid nitrogen and stored at −80°C before the extraction of RNA and protein.

Western blot analysis

About 5 × 106 cells were collected after transfecting for 24 h. The cells were lysed in RIPA buffer (Cell Signaling Technology, Danvers, MA, USA) with the addition of protease inhibitor (phenylmethanesulfonyl fluoride) and phosphatase inhibitor (Na-orthovanadate and NaF). In brief, 8%–10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was applied fractionate equal amounts of total protein which was extracted from cells or tissues. The extracted total protein was electrically transferred onto polyvinylidene difluoride (PVDF) membranes. The PVDF membrane was first incubated with monoclonal antibody against RAGE (1:1000, Abcam), Beclin-1 (1:1000, Abcam), HMGB1 (1:1000, Abcam), LC3AB (1:1000, Abcam), PI3KC-3 (1:1000, Abcam) and GAPDH (1:2000, Boster), and then incubated with appropriate horseradish peroxidase-conjugated secondary antibodies. Enhanced chemiluminescence detection reagents (Thermo Fisher Scientific, Waltham, MA, USA) were applied for the color development of the PVDF membrane, and X-ray films were applied for exposure. The protein levels of target proteins were normalized to the internal control of β-actin.

RNA extraction and quantitative reverse-transcription polymerase chain reaction

TRIzol reagent (Thermo Fisher Scientific, USA) was involved to extract total RNA from the tissue samples. Rever Trace® quantitative polymerase chain reaction (qPCR) RT Kit (TOYOBO Co., Osaka, Japan) was applied according to the manufacturer's instructions. cDNA was synthesized by reverse transcription. Quantitative real-time (QRT)-PCR was performed with IQTMSYBR Green Supermix (Bio-Rad, Hercules, CA, USA). The relative levels of HMGB1/RAGE, LC3, Beclin-1, and PI3K in RCC tissues and adjacent nontumorous samples were calculated with the 2ΔΔCT method. The primers were purchased from Sangon Biotech Co., Ltd (Shanghai). The sequence of primers was as follows: HMGB1 forward: 5′-AGTGCTCAGAGAGGTGGA-3′, HMGB1 reverse: TTTGGGAGGGATATAGGT; RAGE forward: 5GB1 forward: 5′-AGTGCTCAGAGAGGTGGA-3′, HMGB1 reverse: TTTGGGAGGGATATAGGT; RAGE forward: clear cell renal cell carcinomacarcnal cell carcarcCGCGAT-3rward: 5′-AGTGCTCAGAGAGGTGGA-3′, TACTGTTCT-3′, Beclin 1 reverse: 5′-TGTCTTCAATCTTGCCTT-3′; PI3K forward: 5′-CTCTAAACCCTGCTCATC-3GCTPI3K reverse: 5′-CTTGCGTAAATCATCCC-3′.

High-mobility group box 1 silencing and overexpression in the A498 and ACHN cell lines

The cells were seeded into 6-well plates (2.5 × 105 cells/well) and cultured overnight before transfection. A498 and ACHN cells were stably transfected with siRNAs directed against HMGB1 (HMGB1-siRNAs; GenePharma, Shanghai, China) or nontargeted control siRNA (GenePharma, Shanghai, China) with Lipofectamine 2000 (Thermo Fisher Scientific, Waltham, MA, USA). The vector control and pcDNA3.1-HMGB1 plasmid were also transfected into cells with Lipofectamine 2000 according to the manufacturer's instructions. After 6 h of transfection, culture media containing the reagent mixture were removed and replaced with a fresh complete medium, and then the cells were applied for further experiments. Anti-RAGE neutralizing antibody (soluble RAGE [sRAGE]) was provided by Abcam (Cambridge, UK).

Immunofluorescence

Immunofluorescence was performed on paraffin-embedded tissues. Briefly, sections were incubated with primary antibodies of RAGE, CD34, HMGB1, LC3, Beclin1, PI3K (Abcam, Cambridge, MA, USA) overnight. Sections were then washed with PBS and incubated with Alexa Fluor–conjugated secondary antibodies (Scigebio, Shanghai, China) and DAPI (Beyotime Biotech, Nantong, China). Images were taken with a NIKON ECLIPSE TI-SR photomicroscope (×200).

Statistical analysis

Statistical analysis was performed with SPSS 19.0 (SPSS, Chicago, IL, USA). Bar graphs were drawn with GraphPad Prism 7 (GraphPad Software, Inc., La Jolla, CA, USA). All the data were expressed as mean values ± standard deviation. A paired Student's t-test was applied to assess differences between two groups. P <0.05 indicated statistical significance. All the experiments were performed in triplicates.


 > Results Top


The protein expression of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K in ccRCC samples and adjacent normal tissues

The protein expression was evaluated in 12 pairs of histologically confirmed ccRCC samples and adjacent normal tissues. First, the expression of HMGB1/RAGE, LC3, Beclin-1, PI3K in clear cell RCC samples, and adjacent normal tissue were analyzed to explore the relationship between the expression of HMGB1/RAGE and autophagy. Growing evidence suggested that HMGB1/RAGE played an important role in the carcinogenesis process.[12],[22] Consistent with the results of previous reports, we found that the expression of HMGB1 in ccRCC samples (0.6138 ± 0.2394) was much higher than that of in the adjacent normal tissues [0.2247 ± 0.1772, [Figure 1]. Similarly, the expression of RAGE in ccRCC samples (0.5467 ± 0.1275) was much higher than that of in the adjacent normal tissues [0.2803 ± 0.1436, [Figure 1]. Similarly, the expression of LC3 in ccRCC samples (0.4994 ± 0.2334) was also much higher than that of in the adjacent normal tissues [0.1293 ± 0.0739, [Figure 1], as well as the expression of Beclin-1 (1.4572 ± 0.6087 compared with 0.6501 ± 0.1837) and PI3K (1.2629 ± 0.5330 compared with 0.7201 ± 0.2783).
Figure 1: The expressions of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, PI3K were evaluated in clear cell renal cell carcinoma samples and adjacent normal tissues. (a) The expression of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K in clear cell renal cell carcinoma samples and adjacent normal tissues were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/immunoblotting with corresponding antibodies. GAPDH was applied as an internal control. These experiments were repeated in triplicate. (b) Protein expression levels (relative to GAPDH) in clear cell renal cell carcinoma samples and adjacent normal tissues were determined. The data were expressed as mean ± standard deviation for three replicates

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The mRNA expressions of high-mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K in ccRCC samples and adjacent normal tissues

The mRNA expression of HMGB1/RAGE, LC3, Beclin-1, and PI3K was evaluated with qRT-PCR. We found that the mRNA expression of HMGB1 in ccRCC samples (1.1978 ± 0.8004) was higher than that of in the adjacent normal tissues [0.8093 ± 0.8768, [Figure 2]. Similarly, the expression of RAGE in ccRCC samples (1.7319 ± 0.9643) was much higher than that of in adjacent normal tissues [0.8759 ± 0.7078, [Figure 2]. The expression of LC3 in ccRCC samples (1.5504 ± 0.6506) was also much higher than that of in adjacent normal tissues [0.7423 ± 0.3899, [Figure 1], as well as the expression of Beclin-1 (1.4572 ± 0.6087 compared with 0.6501 ± 0.1837) and PI3K (1.2629 ± 0.5330 compared with 0.7201 ± 0.2783).
Figure 2: The mRNA levels of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K in clear cell RCC samples and adjacent normal tissues were detected by quantitative real-time polymerase chain reaction. Total RNA from the tissue samples was extracted with TRIzol reagent. cDNA was synthesized by reverse transcription using Rever Trace® quantitative polymerase chain reaction RT Kit. Then, the relative levels of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1 and PI3K in renal cell carcinoma and adjacent nontumorous were calculated with the 2ΔΔCT method *P < 0.05, **P < 0.01

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The expression of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K in ccRCC samples and adjacent normal tissue by immunofluorescence

The relationship of HMGB1/RAGE and autophagy was also confirmed with immunofluorescence. Consistent with the previous results, HMGB1/RAGE expression in the ccRCC samples was much higher than that of in the adjacent normal tissues as shown in [Figure 3]. We also found that the expression of the autophagic protein LC3, Beclin-1, PI3K in ccRCC samples was much higher than that of in adjacent normal tissues.
Figure 3: Representative photographs of immunofluorescence staining of high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1 and PI3K in clear cell renal cell carcinoma samples and adjacent normal tissues. The tumor and normal tissues of patients were stained with high mobility group box 1/receptor for advanced glycation end-product, LC3, Beclin-1, and PI3K. The photographs were taken at the magnifications of ×200

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The regulation of receptor for advanced glycation end-product and autophagic protein expression with high-mobility group box 1 in human renal cell carcinoma cell lines

A key regulator of autophagy in the TME was Damage Associated Molecular Pattern molecules, such as HMGB1 and its receptor RAGE.[23],[24] Therefore, the interaction of HMGB1 and RAGE was analyzed with qRT-PCR. We found that, after the knockdown of the HMGB1, down-regulated the mRNA expression of RAGE, and autophagic protein LC3 and Beclin1 would be down-regulated shown in [Figure 4]a and [Figure 4]b. While the level of RAGE would be up-regulated with the overexpressed HMGB1 shown in [Figure 4]a and [Figure 4]b. Moreover, the mRNA expression of autophagic protein LC3 and Beclin-1 was also remarkably upregulated with the overexpression of HMGB1.
Figure 4: High mobility group box 1 regulated receptor for advanced glycation end-product and autophagic protein mRNA expression in human renal cell carcinoma cell lines. (a) The expression of high mobility group box 1, receptor for advanced glycation end-product, LC3, and Beclin1 in the A498 cell line were analyzed by quantitative real-time polymerase chain reaction. (b) The expression of high mobility group box 1, receptor for advanced glycation end-product, LC3, and Beclin1 in the ACHN cell line were analyzed by quantitative real-time polymerase chain reaction. Data were presented as mean ± standard deviation for three independent experiments. *P < 0.05, **P < 0.01, versus Con-siRNA group; ##P < 0.01, versus Con-Vec group; ^^P < 0.01, versus receptor for advanced glycation end-product group

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The relationships of HMGB1, RAGE, and LC3 were also further analyzed with immunofluorescence. As shown in [Figure 5], there were decreased expression levels of LC3 and RAGE in the HMGB1-siRNA1 group, the expression levels of LC3 and RAGE were up-regulated with the overexpression of HMGB1. In addition, the HMGB1-Vec+sRAGE group showed an increased expression level of LC3, while it was decreased compared to that of in the sRAGE group. These results suggested that HMGB1 played an important role in the RAGE and autophagic protein expression in RCC cells.
Figure 5: High mobility group box 1 regulated receptor for advanced glycation end-product and LC3 expression in human renal cell carcinoma cell lines. The expression of LC3 (red) and receptor for advanced glycation end-product (green) in the (a) A498 cell line (b) ACHN cell line were examined by immunofluorescence analysis and observed with a confocal microscope. DAPI was a blue tint to the nucleus. The photographs were taken at the magnifications of ×200. The representative result was shown from three repeats with a similar pattern

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 > Discussion Top


Originally, RAGE was defined as a RAGE. Then, it was found to be the receptor of many other molecules involved in innate immunity, including amyloid-β peptide, the S100 family of proteins, and HMGB-1.[16] Emerging reports have demonstrated the important roles of RAGE in the pathogenesis of multiple human physical disorders including malignant tumors.[22],[25] In the past a few years, RAGE was found to make important effects in the RCC progression. RAGE was proved to be a potential prognostic biomarker for RCC.[26] In this research, RAGE was also found to be upregulated in ccRCC tumor tissues compared with that of in adjacent normal tissue.

HMGB1 was a conserved protein with various physiological function with the main receptors of RAGE and TLR. RAGE and TLR were confirmed to be on the surface of endothelial cells and immune system cells. Once being released to the extracellular space, HMGB1 would become a proinflammatory cytokine, then activate the formation of new blood microvessels, improve the cell metastasis, enhance the inflammatory conditions, and regulate cell growth. HMGB1 protein also played an important role in regenerating the impaired tissues and stimulating autophagy. HMGB1 played a potential role in anticancer therapy. In the immunohistochemical results, HMGB1 expression in the pathological samples of patients confirmed that ccRCC was related to the PT1b classification and tumor grade.[27],[28] In ccRCC, there was a methylation of HMGB1 at lysine 112, which affected its binding capacity with DNA, as well as mediating its translocation. It also reported that the development and progression of ccRCC would be promoted with HMGB1 through the activation of ERK1/2, which was partially regulated by RAGE.[29] Consistent with the previous results, our data confirmed that the expression level of HMGB1 was higher in the ccRCC tumor tissues compared with that of in the adjacent normal tissues.

As a nonchromosomal DNA binding protein, HMGB1 has taken part in a variety of cellular biological processes, including cell differentiation, cell autophagy, and cell invasion.[30],[31] HMGB1 also played important roles in the inflammatory reactions through regulating the expression of NFκB,[32] as well as inducing the upregulation of c-myc which contributed to tumor malignancies. For the autophagy, HMGB1 was involved at several levels. First, HMGB1 mediated the expression of heat shock protein β-1, which was a key player in the dynamic intracellular trafficking during autophagy and mitophagy.[33] Moreover, HMGB1 could destroy the Beclin-1-B cell lymphoma-2 complex and activate autophagy through the interaction with Beclin-1.[34] Therefore, the autophagic protein LC3, Beclin-1, and PI3K were investigated in this study. Our data demonstrated that the expression levels of autophagic proteins were also upregulated in ccRCC tumor tissues compared with those of in adjacent normal tissues. Through the knockdown and overexpression of HMGB1/RAGE, it also confirmed the critical roles of HMGB1/RAGE in the regulation of autophagic protein.


 > Conclusion Top


Autophagic protein, HMGB1, and its receptor RAGE were increased in ccRCC tumor tissues. We suggested that the interaction between HMGB1 and RAGE initiated signaling such as ERK1/2 phosphorylation, NF-kB, and MAPK, which contributed to autophagy in ccRCC. These findings collectively implicated that HMGB1 and RAGE might serve as a therapeutic target for future treatment on ccRCC. As far as we know, the current RAGE-targeted antineoplastic therapies involved the treatments with small molecule inhibitors,[35],[36] sRAGE and nonviral gene delivery vectors.[37] Nowadays, several inhibitors of HMGB1 have been investigated, which could be applied in anticancer therapy.[17]

These RAGE suppressants and HMGB1 inhibitors play important roles in the regulation of autophagy, which might be potential candidate drugs in inhibiting cancer recurrence during chemotherapy.

Acknowledgments

We would like to acknowledge special thanks to the faculty of the Department of Pathology, the Fifth Hospital of Sijiazhuang.

Financial support and sponsorship

This study was supported by Wenzhou Municipal Science and Technology Bureau (Y20160032, Y20160127), Zhejiang medical and health science and technology project (2017KY454).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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