MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Selection
2.2. Study Objectives and Endpoints
2.3. MiRNA Extraction
2.4. mRNA Extraction
2.5. Selection of miRNAs and Genes
2.6. Clinical Data
2.7. Statistical Analysis
3. Results
3.1. Included Patients
3.2. MiRNAs Associated with Longer or Shorter Time-to-Bone-Metastasis
3.3. Correlation of miRNA with Gene Expression
3.4. Correlation of miRNA with Clinical Outcome
3.5. Correlation of mRNA Expression with TTBM and OS
4. Discussion
4.1. miRNA Associated with Longer TTBM
4.2. miRNA Associated with Shorter TTBM
4.3. miRNA-mRNA Associations
4.4. Limitations and Strengths of Our Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Selected miRNAs | ||
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let-7a-3p [18,19], let-7a-5p [19,20], let-7g-3p [19], let-7g-5p [19], miR-10b-3p [21,22], miR-10b-5p [21,22], miR-15b-3p [23], miR-15b-5p [23], miR-16-1-3p [24], miR-16-2-3p [24], miR-16-5p [24], miR-17-3p [25], miR-17-5p [26], miR-19a-3p [27], miR-20a-5p [28,29], miR-21-3p [30,31], miR-21-5p [26,30], miR-23a-3p [32,33,34], miR-27a-3p [26,34], miR-28-3p [35], miR-30a-3p [36], miR-30a-5p [36], miR-30b-3p [36], miR-30c-5p [36], miR-30d-3p [36], miR-30d-5p [36], miR-30e-3p [36], miR-30e-5p [36], miR-31-5p [26], miR-33a-5p [37], miR-34a-5p [38], miR-34c-5p [39], miR-125a-3p [26], miR-125a-5p [26], miR-126-5p [26,40], miR-133a-3p [41], miR-135a-5p [42], miR-138-5p [43], miR-139-3p [44,45], miR-139-5p [46], miR-141-3p [47], miR-142-3p [48,49], miR-142-5p [48], miR-143-3p [50,51], miR-143-5p [50], miR-145-3p [50,52], miR-145-5p [50,52], miR-148a-3p [27,53], miR-155-5p [54,55], miR-182-5p [56,57], miR-190a-5p [24], miR-190b [24], miR-200a-3p [58], miR-200a-5p [58], miR-200b-3p [58], miR-200b-5p [58], miR-200c-3p [58], miR-203a-3p [42], miR-204-5p [59], miR-210-3p [55,60], miR-211-5p [59], miR-214-3p [61], miR-214-5p [61], miR-218-5p [62], miR-223-3p [47], miR-223-5p [47], miR-296-5p [27], miR-326 [63], miR-335-3p [18], miR-335-5p [64], miR-378a-3p [24], miR-379-5p [65], miR-409-3p [65], miR-409-5p [65], miR-503-5p [24], miR-542-3p [66], miR-542-5p [67], miR-543 [68] | ||
Selected genes | ||
Protective for BM | ||
BMP7 | Bone Morphogenetic Protein 7 | Binds BMPR2 receptor on tumor cells and enhances tumor cell dormancy through ERK/MAPK signaling [69]. |
BMPR2 | Bone Morphogenetic Protein Receptor Type 2 | Promotes tumor cell dormancy in bone [40]. Inversely correlated with prostate BM occurrence [70]. |
FOS | Fos Proto-Oncogene | Transcription factor for osteoclastogenesis [71]. |
NOS3 | Nitric Oxide Synthase 3 | Decreases invasiveness [68]. |
NOTCH1 | Notch Receptor 1 | Involved in oncogenesis [40]. |
PDCD4 | Programmed Cell Death 4 | Represses osteoclastogenesis [71]. Downregulation in NSCLC potentially enhances BM [30]. |
SATB2 | Special AT-Rich Sequence-Binding Protein 2 | Promotes osteoblastogenesis and bone regeneration [72]. Downregulation is associated with metastasis in ccRCC [72]. |
SRCIN1 | SRC Kinase Signaling Inhibitor 1 | Inhibits osteoclast differentiation [28]. |
SMAD2 | SMAD Family Member 2 | Decreases invasiveness. Component of the TGFβ pathway. In BC cells, loss of SMAD2 increases BM potential [73]. |
SMAD4 | SMAD Family Member 4 | Decreases invasiveness [40,74]. |
OPG | Osteoprotegerin | Decoy receptor preventing RANKL-RANK signaling [9]. |
Associated with BM | ||
CD44 | Cluster of differentiator 44 | Promotes invasiveness [40,75]. |
CDH11 | Cadherin 11 | Promotes osteomimicry [36]. |
CTGF | Connective Tissue Growth Factor | Stimulates osteoclasts [40]. |
CXCL8 | C-X-C Motif Chemokine Ligand 8 | Promotes osteoclastogenesis [76]. |
CXCR4 | C-X-C Motif Chemokine Receptor 4 | Promotes metastasis to osteogenic niches [40,77]. |
DKK1 | Dickkopf WNT Signaling Pathway Inhibitor 1 | Osteoclast inhibitor [40]. |
ELK1 | ETS Transcription Factor ELK1 | Promotes osteoblast differentiation [44]. Inducer of c-FOS proto-oncogene and part of ERK/MSK1/Elk-1/Snail signaling pathway (enhances cancer proliferation) [78]. |
IL11 | Interleukin 11 | Stimulates osteoclasts [40]. |
ITGA3 | Integrin Subunit Alpha 3 | Promotes invasiveness [40,75]. |
ITGA5 | Integrin Subunit Alpha 5 | Involved in invasiveness [36], anchors cancer cells to bone [79]. |
ITGB3 | Integrin Subunit Beta 3 | Integrin promoting osteomimicry and osteolytic metastases [80]. |
RUNX2 | Runt-Related Transcription Factor 2 | TF essential in osteoblastogenesis and osteomimicry in PC and BC [42]. |
SMAD1 | SMAD Family Member 1 | Osteoblast differentiation [81]. |
TCF7 | Transcription Factor 7 | Involved in BM, part of the Wnt/beta-catenin signaling pathway [38]. |
TGIF2 | TGF-Beta-induced transcription factor 2 | Pro-osteoclastic factor [82]. |
TGFB1 | Transforming Growth Factor Beta 1 | Stimulates pro-osteoclastic factor production in cancer cells [40]. |
RANKL | Receptor Activator Of Nuclear Factor Kappa B Ligand | Promotes osteoclastogenesis [10]. |
RANK | Receptor Activator Of Nuclear Factor Kappa B | Osteoclast activation [83]. |
All Patients | n = 128 | |
---|---|---|
Gender: male | 86 | 67% |
Median age at diagnosis (years) | 62 | IQR: 55–69 |
Median OS after diagnosis (months) | 49 | IQR: 21–103.25 |
Median OS after stage IV (months) | 34 | IQR: 16.5–62.25 |
Bone metastasis | ||
BM at time of nephrectomy (n) | 22 | 17.2% |
Metachronous BM (n) | 106 | 82.8% |
Median time to metachronous BM (months) | 34 | IQR: 24.25–100.5 |
IMDC risk group at start of first-line therapy | ||
Favorable (n) | 14 | 11% |
Intermediate (n) | 81 | 63% |
Poor (n) | 33 | 26% |
First-line targeted therapy | ||
Sunitinib (n) | 68 | 53% |
Pazopanib (n) | 31 | 24% |
Sorafenib (n) | 11 | 9% |
Temsirolimus (n) | 9 | 7% |
Nivolumab-Ipilimumab (n) | 6 | 5% |
Other (n) | 3 | 2% |
miRNAs Associated with Longer TTBM | |||
---|---|---|---|
miR-30b-3p | BM promoting genes: inverse correlation | ||
RANKL | rho = −0.33; p = 0.002 | miR-30 family inhibits BM in BC by targeting CXCL8 [36] | |
ITGA3 | rho = −0.31; p = 0.003 | ||
TCF7 | rho = −0.25; p = 0.018 | ||
CD44 | rho = −0.24; p = 0.021 | ||
CXCL8 | rho = −0.21; p = 0.045 | ||
miR-139-3p | BM protective genes: positive correlation | ||
NOTCH1 | rho = 0.29; p = 0.005 | ||
BMPR2 | rho = 0.27; p = 0.011 | ||
BM promoting genes: inverse correlation | |||
TCF7 | rho = −0.23; p = 0.027 | ||
ITGA3 | rho = −0.22; p = 0.038 | ||
miR-204-5p | BM protective genes: positive correlation | ||
FOS | rho = 0.28; p = 0.007 | ||
BMPR2 | rho = 0.32; p = 0.003 | ||
SATB2 | rho = 0.34; p = 0.001 | ||
SMAD4 | rho = 0.35; p = 0.001 | ||
BM promoting genes: inverse correlation | |||
CD44 | rho = −0.55; p < 0.001 | miR-204 regulates RUNX2 expression and MSC differentiation [85]. | |
RANKL | rho = −0.42; p < 0.001 | Sponging of miR-204-5p by lncRNA SNHG4 upregulates RUNX2 and promotes tumor progression in RCC [86]. | |
ITGA3 | rho = −0.42; p < 0.001 | miR-204-5p inhibits TGF-β-induced IL11 production in BM cells of BC [59]. | |
RUNX2 ° | rho = −0.41; p < 0.001 | miR-204 inhibits growth and motility of CRC cells by CXCL8 downregulation [87]. | |
ITGA5 | rho = −0.36; p = 0.001 | ||
CDH11 ° | rho = −0.39; p < 0.001 | ||
TGFB1 | rho = −0.33; p = 0.002 | ||
CXCL8 | rho = −0.3; p = 0.005 | ||
TCF7 | rho = −0.36; p < 0.001 | ||
CTGF | rho = −0.26; p = 0.014 | ||
miR-542-5p | BM protective genes: positive correlation | ||
SATB2 | rho = 0.34; p = 0.001 | miR-542-5p increases SMAD2 expression levels in ICU weakness [88]. | |
SMAD2 | rho = 0.29; p = 0.006 | ||
BM promoting genes: inverse correlation | |||
TCF7 | rho = −0.37; p < 0.001 | ||
RUNX2 | rho = −0.31; p = 0.003 | ||
CD44 | rho = −0.32; p = 0.002 | ||
CXCR4 | rho = −0.21; p = 0.044 | ||
miRNAs Associated With Shorter TTBM | |||
miR-21-5p | BM protective genes: inverse correlation | ||
SATB2 | rho = −0.22; p = 0.04 | ||
SMAD4 | rho = −0.24; p = 0.026 | ||
BM promoting genes: positive correlation | |||
TCF7 | rho = 0.27; p = 0.011 | ||
CD44 * | rho = 0.25; p = 0.018 | ||
ITGA3 | rho = 0.29; p = 0.005 | ||
miR-21-3p | BM protective genes: inverse correlation | ||
FOS | rho = −0.45; p < 0.001 | miR-21 deficiency results in cFOS upregulation in periodontal tissues [89]. | |
BMPR2 | rho = −0.42; p < 0.001 | BMPR2 is directly targeted by miR-21 in PC cells [90]. | |
SATB2 | rho = −0.31; p = 0.003 | miR-21-3p is involved in proliferation and invasion through SMAD4/Erk signaling in CRC [31]. | |
SMAD4 | rho = 0.22; p = 0.043 | ||
BM promoting genes: positive correlation | |||
ITGA3 | rho = 0.42; p < 0.001 | TGFB1 signaling increases miR-21 expression in renal fibrosis [91]. | |
RANKL | rho = 0.38; p < 0.001 | ||
CD44 * | rho = 0.37; p < 0.001 | ||
TGFB1 | rho = 0.25; p = 0.018 | ||
CXCL8 * | rho = 0.22; p = 0.043 | ||
miR-28-3p | BM protective genes: inverse correlation | ||
SATB2 | rho = −0.24; p = 0.022 | ||
SRCIN1 | rho = −0.22; p = 0.038 | ||
BM promoting genes: positive correlation | |||
CXCR4 | rho = 0.24; p = 0.025 | ||
miR-34c-5p | BM protective genes: inverse correlation | ||
SATB2 ° | rho = −0.23; p = 0.033 | miR-34s inhibit osteoblast proliferation and differentiation in mouse by targeting SATB2 [92]. | |
FOS | rho = −0.26; p = 0.015 | SATB2 targeted by miR-34c-5p suppresses proliferation and metastasis attenuating EMT in CRC [39]. | |
BM promoting genes: positive correlation | |||
CD44 | rho = 0.3; p = 0.004 | ||
ITGA3 | rho = 0.38; p < 0.001 | ||
RANK | rho = 0.21; p = 0.047 | ||
TGFB1 | rho = 0.26; p = 0.015 | ||
miR-23a-3p | BM protective genes: positive correlation | ||
BMPR2 * | rho = 0.23; p = 0.027 | ||
BM promoting genes: inverse correlation | |||
CXCL8 * | rho = −0.25; p = 0.017 | ||
ELK1 | rho = −0.24; p = 0.021 | ||
miR-20a-5p | BM protective genes: inverse correlation | ||
OPG * | rho = −0.21; p = 0.044 | ||
BM protective genes: positive correlation | |||
PDCD4 ° | rho = 0.28; p = 0.009 | ||
BM promoting genes: inverse correlation | |||
ITGB3 | rho = −0.23; p = 0.03 | ||
BM promoting genes: positive correlation | |||
IL11 | rho = 0.27; p = 0.011 | RUNX2 is positively correlated with miR-20a-5p in adipose SC during osteogenic differentiation [93]. | |
TCF7 | rho = 0.26; p = 0.012 | ||
RUNX2 | rho = 0.22; p = 0.035 | ||
miR-335-3p | BM protective genes: inverse correlation | ||
OPG | rho = −0.23; p = 0.03 | ||
BM promoting genes: positive correlation | |||
CD44 | rho = 0.31; p = 0.003 | ||
ITGA5 | rho = 0.29; p = 0.007 | ||
RANKL | rho = 0.22; p = 0.04 | ||
CDH11 | rho = 0.36; p = 0.001 | ||
ITGA3 | rho = 0.27; p = 0.011 | ||
TGFB1 | rho = 0.29; p = 0.006 | ||
TCF7 | rho = 0.35; p = 0.001 | ||
RUNX2 | rho = 0.3; p = 0.004 | ||
miR-182-5p | BM protective genes: inverse correlation | ||
SATB2 *,° | rho = −0.29; p = 0.006 | microRNA-182 targets SATB2 to promote CRC proliferation and metastasis [94]. | |
BMPR2 * | rho = −0.28; p = 0.009 | ||
OPG | rho = −0.28; p = 0.007 | ||
BM promoting genes: positive correlation | |||
CD44 | rho = 0.37; p < 0.001 | ||
CDH11 * | rho = 0.25; p = 0.02 | ||
ITGA3 | rho = 0.37; p < 0.001 | ||
IL11 * | rho = 0.21; p = 0.046 | ||
CXCL8 | rho = 0.32; p = 0.002 | ||
TCF7 | rho = 0.34; p = 0.001 | ||
RUNX2 | rho = 0.27; p = 0.011 | ||
miR-27a-3p | BM protective genes: inverse correlation | ||
BMP7 * | rho = −0.29; p = 0.007 | ||
BM protective genes: positive correlation | |||
PDCD4 | rho = 0.23; p = 0.031 | ||
BM promoting genes: inverse correlation | |||
CXCL8 * | rho = −0.26; p = 0.013 |
miRNA | OS Since Diagnosis | PFS on VEGFR-TKIs | OS on VEGFR-TKIs | |||
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
Longer time to bone metastasis | ||||||
miR-204-5p | 0.73 (0.65–0.82) | <0.001 | 0.84 (0.74–0.94) | 0.003 | 0.81 (0.72–0.92) | 0.001 |
miR-30b-3p | 0.93 (0.78–1.10) | 0.386 | 1.07 (0.88–1.31) | 0.496 | 0.99 (0.81–1.21) | 0.921 |
miR-542-5p | 0.85 (0.69–1.05) | 0.133 | 0.96 (0.77–1.20) | 0.728 | 0.89 (0.71–1.11) | 0.296 |
miR-139-3p | 0.86 (0.73–1.00) | 0.057 | 0.91 (0.76–1.09) | 0.321 | 0.87 (0.73–1.03) | 0.105 |
Shorter time to bone metastasis | ||||||
miR-21-5p | 1.69 (1.31–2.18) | <0.001 | 1.14 (0.88–1.47) | 0.327 | 1.29 (1.01–1.65) | 0.043 |
miR-21-3p | 1.50 (1.31–2.18) | <0.001 | 1.24 (1.04–1.48) | 0.016 | 1.35 (1.13–1.61) | 0.001 |
miR-28-3p | 1.38 (0.98–1.93) | 0.064 | 1.01 (0.70–1.47) | 0.959 | 1.04 (0.72–1.50) | 0.823 |
miR-34c-5p | 1.31 (1.16–1.48) | <0.001 | 1.19 (1.05–1.35) | 0.007 | 1.27 (1.11–1.44) | <0.001 |
miR-23a-3p | 1.05 (0.83–1.33) | 0.697 | 0.98 (0.75–1.30) | 0.903 | 1.01 (0.76–1.34) | 0.953 |
miR-20a-5p | 1.12 (0.91–1.39) | 0.279 | 0.95 (0.77–1.19) | 0.680 | 0.94 (0.75–1.18) | 0.598 |
miR-335-3p | 1.22 (1.06–1.41) | 0.005 | 1.10 (0.95–1.26) | 0.193 | 1.11 (0.96–1.28) | 0.155 |
miR-182-5p | 1.25 (1.09–1.43) | 0.002 | 1.11 (0.96–1.29) | 0.145 | 1.16 (1.01–1.34) | 0.040 |
miR-27a-3p | 1.13 (0.87–1.47) | 0.351 | 0.87 (0.65–1.17) | 0.365 | 1.03 (0.77–1.39) | 0.831 |
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Kinget, L.; Roussel, E.; Lambrechts, D.; Boeckx, B.; Vanginderhuysen, L.; Albersen, M.; Rodríguez-Antona, C.; Graña-Castro, O.; Inglada-Pérez, L.; Verbiest, A.; et al. MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma. Cancers 2021, 13, 1554. https://doi.org/10.3390/cancers13071554
Kinget L, Roussel E, Lambrechts D, Boeckx B, Vanginderhuysen L, Albersen M, Rodríguez-Antona C, Graña-Castro O, Inglada-Pérez L, Verbiest A, et al. MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma. Cancers. 2021; 13(7):1554. https://doi.org/10.3390/cancers13071554
Chicago/Turabian StyleKinget, Lisa, Eduard Roussel, Diether Lambrechts, Bram Boeckx, Loïc Vanginderhuysen, Maarten Albersen, Cristina Rodríguez-Antona, Osvaldo Graña-Castro, Lucía Inglada-Pérez, Annelies Verbiest, and et al. 2021. "MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma" Cancers 13, no. 7: 1554. https://doi.org/10.3390/cancers13071554