Research ArticleExperimental Studies

The Regulatory Role of Nuclear Respiratory Factor 1 in Bladder Cancer Cells

YEN-HSI LEE, RICHARD C. WU, HSING-CHIA MAI, WEI-LUN HUANG, CHUN-HSIEN WU, YU-LIN YANG, PEI-FANG HSIEH and VICTOR C. LIN
Anticancer Research April 2023, 43 (4) 1521-1531; DOI: https://doi.org/10.21873/anticanres.16301

Abstract

Background/Aim: Nuclear respiratory factor 1 (NRF1) is a key mediator of genes involved in mitochondrial biogenesis and the respiratory chain; however, its role in bladder cancer remains unknown. Transitional cell carcinoma, also known as urothelial cell carcinoma, is the most common type of bladder cancer resistant to chemotherapy. An established high-grade and invasive transitional cell carcinoma line from patients with urinary bladder cancer, known as T24, has been extensively used in cancer research. In this study, we aimed to investigate the mechanisms through which NRF1 regulates proliferation and cell migration of bladder cancer cells using the T24 cell line. Materials and Methods: Cells were transfected with plasmid cloning DNA for NRF1 to evaluate the effect of NRF1 overexpression on bladder cancer cells. Western blot was used to examine epithelial and mesenchymal markers (E-cadherin and α-smooth muscle actin), transcriptional regulators for epithelial–mesenchymal transition (snail family transcriptional repressors), components of transforming growth factor-β1/SMADs signaling, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end-products (RAGE). The in situ expression of E-cadherin, α-smooth muscle actin and SMAD7 was determined using immunofluorescence staining. Cell migration capacity was assessed by wound-healing assay. Results: Transfection with NRF1 expression vector repressed the migration capacity of bladder cancer cells, diminishing HMGB1/RAGE expression and reducing transforming growth factor β-associated epithelial–mesenchymal transition in T24 cells. Conclusion: Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments for bladder cancer.

Key Words:

Transitional cell carcinoma (TCC), also known as urothelial cell carcinoma, is the most common type of bladder cancer resistant to chemotherapy (1-4), and comprises muscle-invasive and non-muscle-invasive types (5, 6).

Muscle-invasive bladder cancer is often treated with hormone therapy, radiotherapy, chemotherapy, and surgery, despite their safety and therapeutic effect remaining undetermined. In fact, muscle-invasive bladder cancer frequently results in poor prognosis, high rates of metastasis, and death (7-11). Intravesical instillation chemotherapy is used to reduce the recurrence rate; however, there are serious complications, such as hematuria, allergy, urinary pain, and other toxic side-effects (12-15). Approximately 30% of patients with superficial cancer develop invasive and metastatic pathologies (6, 13). Hence, a high-grade and invasive TCC cell line, T24, was established and used to study cancer aggressiveness (16, 17) in order to develop a new strategy with minimal adverse reactions to treat bladder cancer.

Transforming growth factor-β (TGF-β)-induced epithelial–mesenchymal transition (EMT) has long been known to be implicated in cancer stemness, which is responsible for tumor recurrence, invasiveness, and drug resistance (18-20). It has been demonstrated that TGF-β stimulation led to acquisition of mesenchymal phenotype in epithelial cells and caused cancer cells to favor invasion and metastasis (18, 19). Moreover, aberrant expression of high-mobility group box-1 (HMGB1) is also associated with tumor metastasis and invasion. It has been shown that silencing of HMGB1 increased the expression of the epithelial cell marker E-cadherin and down-regulated the expression of mesenchymal markers α-smooth muscle actin (α-SMA), snail family transcriptional repressor 1 (SNAI1), SNAI2 (SLUG) and receptor for advanced glycation end-products (RAGE) (21, 22). Most importantly, HMGB1 is critical in maintaining cell phenotype during TGF-β1-induced EMT and silencing HMGB1 expression reduced cell metastatic and invasive ability (21, 23).

Mitochondria are indispensable signaling organelles that allow cells to adapt to stress in the environment (24). It comes as no surprise that mitochondrial functions are essential for cancer cell survival and proliferation. Therefore, cancer cells commonly possess mitochondrial gene mutations that do not inactivate mitochondrial energy metabolism but rather alter the biosynthetic state and mitochondrial bioenergetics (25). Most metabolic signaling in cells takes place in the mitochondria or is regulated by mitochondrial activities; thus, knowledge of mitochondrial function is critical to the investigation of cancer cell biogenesis (26, 27). Among various key mediators that control mitochondrial dynamics, nuclear respiratory factor-1 (NRF1) is a transcription factor that appears to exert both protective and inhibitory effects on different types of cancer cells. NRF1 was initially identified as a cytochrome-c activator (28) and is now known as a crucial modulator of mitochondrial functions. It has been found to play a role in histone gene expression and act as a regulator of cell proliferation (29, 30). In addition, a number of genes essential for the proteins implicated in mitochondrial functions and biogenesis (31), mitochondrial replication, gene expression, and protein import and assembly (32-35) are under the regulation of NRF1. In breast cancer cells, overexpression of NRF1 has been shown to inhibit tamoxifen-induced apoptosis (36). In addition, NRF1 increased the expression of cell-cycle genes in extradiol-treated MCF-7 breast cancer cells (37). On the other hand, up-regulation of NRF1 expression by sulforaphane treatment had a tumor-suppressing effect in prostate cancer cells, resulting in reduced cell viability (38). In this study, we evaluated the function of NRF1 in bladder cancer cells regarding their metastatic potential and elucidated the changes of the downstream factors.

We treated T24 cells with plasmid cloning DNA (pcDNA) for NRF1 then investigated the morphology, viability, and migration ability of these cells. In addition, we examined the TGF-β cascade and EMT markers in T24 cells treated with pcDNA-NRF1. These findings hinted at the role of HMGB1/RAGE in TGF-β-regulated EMT in bladder cancer cells.

Materials and Methods

Cell culture. T24, human bladder carcinoma cells (HTB-4, American Type Culture Collection, Manassas, VA, USA) were grown in McCoy’s 5A medium (Sigma-Aldrich Co. Ltd., Poole, Dorset, UK) containing 10% fetal bovine serum (Gibco, Grand Island, NY, USA) and 2% Penicillin–Streptomycin (Hyclone Labs, Logan, UT, USA) and maintained at 37°C with 5% CO2.

Plasmid construction and cell transfection procedure. The cDNA of NRF1 was cloned into pcDNA3.1 plasmid (Clontech Inc., Palo Alto, CA, USA). Recombinant plasmids were transduced using Escherichia coli DH5α cells (Tiangen, Beijing, PR China) and extracted using a plasmid DNA extraction kit (Takara Biotechnology Co., Ltd, Tokyo, Japan). The T24 cells were transfected with 2 μg/ml pcDNA.3.1-NRF1 using Fugene HD Transfection reagent (Roche Molecular Biochemicals, Pleasanton, CA, USA) and incubated at 37°C with 5% CO2 for 24 h according to the manufacturer’s protocol.

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. T24 cells expressing empty vector or pcDNA NRF1 were seeded in 96-well plates (100 μl/well) at a density of 1×104 cells/ml. After 24 h, cells were treated with 10 μl of MTT (ThermoFisher Scientific Inc., Waltham, MA, USA), followed by incubation at 37°C for 2 h. Finally, 100 μl of acidic isopropanol was added to the cells to completely dissolve the formed formazan crystals. The absorbance of the samples was then determined at 590 nm using a microplate reader. The assay was performed in triplicate.

Lactate dehydrogenase (LDH) assay. LDH release was measured using an LDH cytotoxicity detection kit (Clontech Laboratories, Mountain View, CA, USA) to examine the plasma membrane of damaged cells according to the manufacturer’s instructions. Briefly, T24 cells expressing empty vector or pcDNA NRF1 were seeded in a 96-well plate and cultured in 5% CO2 at 37°C overnight. The supernatant was transferred to another clear 96-well plate, and 100 μl of LDH assay kit solution was added to each well and mixed for 30 min. 1% Triton X-100 was used as a positive control for maximum LDH release. Absorbance was then measured at 490 nm (reference wavelength greater than 600 nm).

Wound-healing assay. Cell migration capacity was assessed using a wound-healing assay. Using a silicone two-well culture insert in a 35 mm μ-Dish (ibidi GmbH, Martinsried, Germany), we allowed the cells (1×104) to separate by 500 μm and adhere and spread on the substrate for 24 h. After removing the culture insert, wound closure was photographed and inspected under a microscope at ×40 magnification. For each image, the gap area was measured using Quantity One software (version 4.6.6; Bio-Rad Laboratories, Inc., Hercules, CA, USA). The migration rate was quantified by dividing the change in wound area by the time spent in migration and was expressed as a percentage. To quantify the effects of NRF1 overexpression on migration, the percentage of gap closure after 24 h was analyzed using an inverted phase-contrast microscope at 0 and 24 h. The assays were repeated twice, and each sample was observed in triplicate.

Cell viability examination. To discriminate the viable and dead cells, trypan blue was added to the medium and the cell viability was determined by counting the number of cells that excluded the dye. The percentage of cell viability was calculated using the following formula:

Embedded Image

Western blot analysis. Total cellular proteins from T24 cells expressing empty vector or pcDNA NRF1 were extracted using lysis buffer [1 mM of dithiothreitol, 20 mM of sucrose, 10 mM of KCl, 20 μM of Tris–HCl (pH 7.2), 1.5 mM of MgCl2, 1 mM of EDTA, and 5 μg/ml of aprotinin] for 30 min. Protein concentration was measured using a Bio-Rad protein assay (Bio-Rad Laboratories) according to the manufacturer’s instructions. Protein extracts containing 30-50 μg of proteins were loaded on sodium dodecyl sulfate–polyacrylamide gels and transferred onto polyvinylidene difluoride membranes. Membranes were blocked for 1 h with 5% (w/v) nonfat milk in Tris-buffered saline with Tween® [0.05% (v/v) Tween-20, 20 mM of Tris–HCl, and 1.5 M of NaCl; pH 7] and incubated with the desired antibodies overnight at 4°C. Following incubation with primary antibodies against E-cadherin (ab53033, 1:2,000; Abcam, Cambridge, UK), α-SMA (ab5694, 1:2,000; Abcam), SNAI1 (ab85931; 1:2,000; Abcam), SNAI2 (SLUG) (sc-166476; 1:2,000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), HMGB1 (ab18256; 1:2,000), RAGE (ab216329; 1:2,000), β-actin (A5441, 1:4000; (A5441; Sigma-Aldrich, St. Louis, MO, USA), TGF-β receptor 1 (TGF-β R1) (sc-9048), TGF-β R2 (sc-1700), SMAD family members 1, 2/3, 4 and 7 (sc-11392), and phospho-SMAD2/3 (sc-11769, 1:2,000; Santa Cruz Biotechnology), membranes were incubated with the corresponding horseradish peroxidase-conjugated secondary antibodies (goat anti-mouse IgG and goat anti-rabbit IgG,1:4,000; Cell Signaling Technology, Beverly, MA, USA). The immunoreactive bands produced were developed using a Western-Ready™ ECL Substrate Plus Kit (BioLegend, San Diego, CA, USA) and detected using a MultiGel-21® image system (Tangshan Top Bio Technology, Co., Ltd. Hebei, PR China). The data were analyzed using Quantity One software (version 4.6.6; Bio-Rad Laboratories, Inc.)

Immunofluorescent staining. Cells were blocked and permeabilized with 5% bovine serum (Sigma) and 0.1% Triton-X 100 (Sigma), respectively. The slides were first incubated with primary antibodies (1:2,000) against α-SMA, E-cadherin, and SMAD7, followed by incubation with secondary anti-mouse/rabbit fluorescein isothiocyanate-conjugated antibody (1:200 in 1% bovine serum; Abcam) overnight. Nuclei were stained using 4,6-diamidino-2-phenylindole (Santa Cruz Biotechnology). All images were visualized with an Olympus fluorescence microscope (CK41) (Olympus Corporation, Tokyo, Japan) using ipwin32 software (Image-Pro Plus version no. 6; Media Cybernetics, Inc., Rockville, MD, USA).

Statistical analysis. Statistically significant differences were determined using one-way analysis of variance followed by Tukey’s post hoc test or two-way analysis of variance of repeated measures followed by Bonferroni’s post hoc test. Each experiment was performed at least three times, and representative results are shown. Values in bar graphs are presented as the mean±standard deviation. A p-value of less than 0.05 was considered to indicate a statistically significant difference.

Results

Transfection with pcDNA-NRF1 suppressed cell proliferation and wound-healing capacity of bladder cancer cells. We investigated the role of NRF1 in T24 cells by transfecting cells with pcDNA-NRF1 and observed that cell density and cell–cell contact were decreased (Figure 1A). MTT assay was employed to examine the proliferation and cell viability, and bladder cancer cells transfected with pcDNA-NRF1 showed reduced cancer cell proliferation (Figure 1B). Similarly, LDH cytotoxicity assay demonstrated that T24 cells with pcDNA-NRF1 markedly enhanced LDH release and reduced cell survival (Figure 1C). We used trypan blue exclusion test to determine cell viability and the results indicate the percentage of viable cells was reduced after transfection with pcDNA-NRF1 (Figure 1D). Next, we examined the wound-healing ability of T24 cells using culture inserts and demonstrated the impairment of cell migration with increased NRF1 expression (Figure 1E). These results suggest that NRF1 possesses tumor-suppressive potential in bladder cancer cells.

Figure 1.
Figure 1.

Nuclear respiratory factor 1 (NRF1) reduces the survival and migration capacity of T24 bladder cancer cells. A: T24 cells were transfected with plasmid cloning DNA (pcDNA)-control or pcDNA-NRF1 for 24 h. The cell morphological images show that NRF1 reduced cell-cell contacts. B: Cell proliferation was determined using a 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. C: Lactate dehydrogenase (LDH) release assay was carried out to show that overexpression of NRF1 increased the cytotoxicity of T24 cells. Triton X-100 served as a positive control. D: Cell viability was determined using trypan blue assay. E: Migration capacity was determined using a two-well culture insert. Significantly different at p<0.05 compared to: *control; #pcDNA-control.

EMT diminished after transfection with pcDNA-NRF1. To determine how NRF1 expression affects EMT, western blotting and immunofluorescent staining were used to detect changes of EMT markers. We observed that transfection with pcDNA-NRF1 reduced EMT (Figure 2). Western blotting results demonstrated that pcDNA-NRF1 up-regulated E-cadherin expression and down-regulated that of α-SMA, SNAI1, and SNAI2 (Figure 2A and B). Immunofluorescent staining of E-cadherin and α-SMA showed similar results (Figure 2C). These findings demonstrated that up-regulation of NRF1 may suppress EMT of bladder cancer cells.

Figure 2.
Figure 2.

Epithelial-to-mesenchymal transition is diminished after treatment with plasmid cloning DNA for nuclear respiratory factor 1 (pcDNA-NRF1). T24 cells were transfected with pcDNA-control or pcDNA-NRF1 for 24 h. A: The expression of epithelial-to-mesenchymal transition proteins, E-cadherin, α-smooth muscle actin (α-SMA), snail family transcriptional repressor 1 (SNAI1) and SNAI2 (SLUG), was measured using western blot with β-actin as an internal control. B: Densitometric analysis of western blotting data. C: In situ expression of E-cadherin and α-SMA was detected using immunofluorescence. Magnification was 200×. 4′,6-Diamidino-2-phenylindole was used to detect nuclei. Data are presented as mean±standard deviation from three independent experiments. Significantly different at p<0.05 compared to: *control; #pcDNA-control.

NRF1 regulates bladder cancer progression by modulating TGF-β-related EMT. To verify the association between NRF1 and TGF-β signaling, cells were treated with pcDNA-NRF1 and the expression of TGF-β pathway components was examined (Figure 3). Western blotting results revealed that the expression of TGF-β R1 and R2, as well as SMAD2/3, was decreased in pcDNA-NRF1-treated cells at 24 h, whereas SMAD7 was up-regulated and no change of SMAD4 was observed (Figure 3A and B). Immunofluorescence staining also demonstrated the up-regulation of SMAD7 in NRF1-overepressing cells (Figure 3C). Taken together, these results clearly suggest that up-regulation of NRF1 downregulates cell proliferation and reduces the EMT of T24 bladder cancer cells, possibly through inhibition of TGF-β signaling.

Figure 3.
Figure 3.

Nuclear respiratory factor 1 (NRF1) regulates bladder cancer progression by modulating transforming growth factor-β (TGF-β)-related epithelial-mesenchymal transition. T24 cells were treated with plasmid cloning DNA (pcDNA)-control or pcDNA-NRF1 for 24 h. A: Protein expression levels of TGF-β receptors 1 and 2 (R1 and R2), SMAD family members 2/3, 7, and 4 were determined using western blotting with β-actin as an internal control. B: Densitometric analysis of TGF-β R1, TGF-β R2, SMAD2/3, SMAD 7, and SMAD 4 from western blotting. C: In situ expression of SMAD7 was detected using immunofluorescence staining with primary antibody against SMAD7 together with 4′,6-diamidino-2-phenylindole (blue) to detect nuclei. Significantly different at p<0.05 compared to: *control; #pcDNA-control.

Alteration of HMGB1 and RAGE in NRF1-overexpressing cells. Given that the HMGB1/RAGE axis may modulate TGF-β signaling, we then examined whether this axis was affected by NRF1 overexpression. As expected, the expression levels of HMGB1 and RAGE in pcDNA-NRF1-transfected cells were lower than in the control cells according to the results from Western blot and immunofluorescence staining (Figure 4).

Figure 4.
Figure 4.

Treatment with plasmid cloning DNA for nuclear respiratory factor 1 (pcDNA-NRF1) suppresses epithelial-mesenchymal transition/transforming growth factor-signaling by down-regulating expression of high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE). T24 cells were treated with pcDNA-control or pcDNA-NRF1 for 24 h. A: Protein expression levels of HMGB1 and RAGE were determined using western blotting with β-actin as an internal control. B: Densitometric analysis of HMGB1 and RAGE from western blotting. C: In situ expression of HMGB1 and RAGE was detected using immunofluorescence staining. Cells were stained with primary antibody against HMGB1 and RAGE together with 4′,6-diamidino-2-phenylindole (blue) to detect nuclei. Significantly different at p<0.05 compared to: *control; #pcDNA-control.

Discussion

Bladder cancer mortality rates have increased worldwide (39, 40). It has been shown that mitochondrial gene mutation contributes to tumor growth of bladder cancer (41) and therapeutic efficacy can be enhanced by targeting mitochondrial genome in patients with TCC (42). In fact, the significance of mitochondria in metastasis has been highlighted in various studies (43, 44). Mitochondrial metabolic output markedly influences the aggressiveness of cancer cells, which is associated with EMT. Among various pathways, TGF-β-induced EMT is the most studied. Nevertheless, the molecular mechanism underlying the regulation of mitochondria in the cellular phenotypical changes instigated by TGF-β has not been fully unraveled. In the present study, we assessed the functional role of NRF1, the master regulator of mitochondrial biogenesis, in the expression of TGF-β/SMAD signaling and EMT-related markers. Moreover, we showed that the putative upstream regulators of TGF-β/SMAD pathway, HMGB/RAGE axis, were also affected by NRF1. Our findings suggest that overexpression of NRF1 may inhibit TGF-β-stimulated EMT through suppression of the HMGB1/RAGE axis (Figure 5).

Figure 5.
Figure 5.

Proposed mechanism of the negative regulatory role of nuclear respiratory factor 1 (NRF1) on bladder cancer via down-regulation of high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE). We propose that the bladder cancer-antagonizing effects of NRF1 are exerted via inhibition of the HMGB1-RAGE axis and subsequent repression of transforming growth factor-β (TGF-β)-associated epithelial-mesenchymal transition (EMT) in T24 cells. Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments of bladder cancer.

A number of studies have indicated that serum or urinary HMGB1 can be used as a diagnostic or prognosis biomarker of bladder cancer (45, 46). Aside from being positively correlated with clinicopathological parameters, overexpression of HMGB1 has been found to be markedly related to shorter overall survival of patients with bladder cancer (47) and resistance to radiation of bladder cancer cells (48, 49). Several studies have shown that HMGB1 participated in bladder cancer radioresistance via modulating the tumor immune microenvironment and promoting DNA damage repair as well as autophagy (48, 49). In addition, it has been shown that HMGB1 may be regulated by long non-coding RNA (lncRNA) HCP5/microRNA (miR)-29b-3p axis and be implicated in cell invasion and migration of bladder cancer cells (50). Similarly, other studies showed that HMGB1 participated in the aggressive behavior of bladder cancer under the control of lncRNA NNT-AS1/miR-496 (51), lncRNA NEAT1/miR-410 (52) or lncRNA UCA1/miR-143 axes (53). Here, we showed that HMGB1 may also be modulated by NRF1.

Mitochondrial dysfunction has been thought to be a crucial driver of EMT (54) and a decreased nuclear accumulation of NRF1 in African-American patients with prostate cancer along with mitochondrial dysfunction was reported (55). Although NRF1 may play an oncogenic role in various types of cancer, such as breast cancer (37) and hepatocellular carcinoma (56), it seemed to act as a tumor suppressor in urological cancers. For instance, up-regulation of NRF1 by sulforaphane has been shown to reduce the viability of human prostate cancer PC3 cells (38). Our previous work also demonstrated that NRF1 had an inhibitory effect on the migration and invasive potential of prostate cancer cells (57). In this study, we showed overexpression of NRF1 inhibited cell proliferation and migration of bladder cancer cells, possibly through down-regulation of TGF-β/SMAD pathway as a result of suppression of the HMGB1/RAGE axis. HMGB1 is known to be involved in TGF-β-induced EMT in hypopharyngeal carcinoma cells through RAGE (21), so we postulated that HMGB1/RAGE may be upstream mediators of the TGF-β/SMAD pathway in bladder cancer. In this study, we demonstrated that HMGB1/RAGE expression was affected by NRF1 overexpression. Intriguingly, HMGB1 also appeared to regulate NRF1 expression in pancreatic cancer cells (58). Hence, whether there is a positive loop between NRF1 and HMGB1 which affects mitochondrial dysfunction or even EMT is worthy of investigation. We also showed that the TGF-β/SMAD pathway was inhibited by NRF1 overexpression, which was consistent with a previous study showing NRF1 can interfere with TGF-β signaling (59). Rajasekaran et al. showed that NRF1 is a negative regulator of SMAD4 using HeLa, SiHa, and MCF7 cells (59); however, we did not observe down-regulation of SMAD4 in T24 cells. Further studies are required to elucidate the possible mechanism. Moreover, to better understand the role of NRF1 in bladder cancer, an extensive analysis of an in vivo model is necessary.

Taken together, our results demonstrate that up-regulation of NRF1 may represent an effective therapeutic approach to down-regulating the metastatic potential of invasive TCC via suppression of TGF-β-associated EMT, possibly through inhibition of the HMGB1/RAGE axis.

Acknowledgements

The Authors would like to thank Dr. Wen-Teng Chang (Department of pharmaceutical science and technology, Chung Hwa University of Medical Technology, Taiwan, ROC) for providing the plasmid construct of pcDNA-NRF1. This research was funded by National Science Council Grants, Taiwan (MOST 109-2314-B-650-013-MY2) and E-Da Hospital Research Grants (EDCHP109010, EDPJ109065, EDAHP108033, and EDPJ110070).

Footnotes

  • Authors’ Contributions

    Methodology: Chun-Hsien Wu and Pei-Fang Hsieh; validation: Wei-Lun Huang, Yen-Hsi Lee and Hsing-Chia Mai; investigation and data curation: Yen-Hsi Lee, Richard Chen-Yu Wu and Pei-Fang Hsieh; resources: Hsing-Chia Mai, Yu-Lin Yang and Victor C. Lin; writing–original draft preparation: Pei-Fang Hsieh; writing–review and editing, Chun-Hsien Wu and Yu-Lin Yang; supervision and project administration. Pei-Fang Hsieh, Yu-Lin Yang and Victor C. Lin; funding acquisition, Yen-Hsi Lee, Pei-Fang Hsieh, Yu-Lin Yang and Victor C. Lin. All Authors have read and agreed to the published version of the article.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare.

  • Received December 31, 2022.
  • Revision received January 18, 2023.
  • Accepted February 6, 2023.

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The Regulatory Role of Nuclear Respiratory Factor 1 in Bladder Cancer Cells
YEN-HSI LEE, RICHARD C. WU, HSING-CHIA MAI, WEI-LUN HUANG, CHUN-HSIEN WU, YU-LIN YANG, PEI-FANG HSIEH, VICTOR C. LIN
Anticancer Research Apr 2023, 43 (4) 1521-1531; DOI: 10.21873/anticanres.16301
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