Introduction: BUB1 mitotic checkpoint serine/threonine kinase B encoded by BUB1B gene is a member of the spindle assembly checkpoint family. Several reports have demonstrated that overexpression of BUB1B is associated with cancer progression and prognosis. Objective: This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC). Methods: The expression of BUB1B was determined using immunohistochemistry and bioinformatics analysis in RCC. The effects of BUB1B knockdown on cell growth and invasion were evaluated. We analyzed the interaction between BUB1B, cancer stem cell markers, p53, and PD-L1 in RCC. Results: In 121 cases of RCC, immunohistochemistry showed that 30 (25%) of the RCC cases were positive for BUB1B. High BUB1B expression was significantly correlated with high nuclear grade, T stage, and M stage. A Kaplan-Meier analysis showed that the high expression of BUB1B was associated with poor overall survival after nephrectomy. High BUB1B expression was associated with CD44, p53, and PD-L1 in RCC. Knockdown of BUB1B suppressed cell growth and invasion in RCC cell lines. Knockdown of BUB1B also suppressed the expression of CD44 and increased the expression of phospho-p53 (Ser15). In silico analysis showed that BUB1B was associated with inflamed CD8+, exhausted T-cell signature, IFN-γ signature, and the response to nivolumab. Conclusion: These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC.

1.
Padala
SA
,
Barsouk
A
,
Thandra
KC
,
Saginala
K
,
Mohammed
A
,
Vakiti
A
, et al.
Epidemiology of Renal Cell Carcinoma
.
World J Oncol
.
2020 Jun
;
11
(
3
):
79
87
. .
2.
Bamias
A
,
Escudier
B
,
Sternberg
CN
,
Zagouri
F
,
Dellis
A
,
Djavan
B
, et al.
Current Clinical Practice Guidelines for the Treatment of Renal Cell Carcinoma: A Systematic Review and Critical Evaluation
.
Oncologist
.
2017 Jun
;
22
(
6
):
667
79
. .
3.
Rini
BI
,
Campbell
SC
,
Escudier
B
.
Renal cell carcinoma
.
Lancet
.
2009 Mar 28
;
373
(
9669
):
1119
32
. .
4.
Kotecha
RR
,
Motzer
RJ
,
Voss
MH
.
Towards individualized therapy for metastatic renal cell carcinoma
.
Nat Rev Clin Oncol
.
2019 Oct
;
16
(
10
):
621
33
. .
5.
Lara-Gonzalez
P
,
Westhorpe
FG
,
Taylor
SS
.
The spindle assembly checkpoint
.
Curr Biol
.
2012 Nov 20
;
22
(
22
):
R966
80
. .
6.
Musacchio
A
.
The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics
.
Curr Biol
.
2015 Oct 19
;
25
(
20
):
R1002
18
. .
7.
Dou
Z
,
Prifti
DK
,
Gui
P
,
Liu
X
,
Elowe
S
,
Yao
X
.
Recent Progress on the Localization of the Spindle Assembly Checkpoint Machinery to Kinetochores
. Cells. 2019 Mar 23;8(3):278.
8.
Hanks
S
,
Coleman
K
,
Reid
S
,
Plaja
A
,
Firth
H
,
Fitzpatrick
D
, et al.
Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B
.
Nat Genet
.
2004 Nov
;
36
(
11
):
1159
61
. .
9.
Kapanidou
M
,
Lee
S
,
Bolanos-Garcia
VM
.
BubR1 kinase: protection against aneuploidy and premature aging
.
Trends Mol Med
.
2015 Jun
;
21
(
6
):
364
72
. .
10.
Bolanos-Garcia
VM
,
Blundell
TL
.
BUB1 and BUBR1: multifaceted kinases of the cell cycle
.
Trends Biochem Sci
.
2011 Mar
;
36
(
3
):
141
50
. .
11.
Yuan
B
,
Xu
Y
,
Woo
JH
,
Wang
Y
,
Bae
YK
,
Yoon
DS
, et al.
Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability
.
Clin Cancer Res
.
2006 Jan 15
;
12
(
2
):
405
10
. .
12.
Yamamoto
Y
,
Matsuyama
H
,
Chochi
Y
,
Okuda
M
,
Kawauchi
S
,
Inoue
R
, et al.
Overexpression of BUBR1 is associated with chromosomal instability in bladder cancer
.
Cancer Genet Cytogenet
.
2007 Apr 1
;
174
(
1
):
42
7
. .
13.
Rio Frio
T
,
Lavoie
J
,
Hamel
N
,
Geyer
FC
,
Kushner
YB
,
Novak
DJ
, et al.
Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia
.
N Engl J Med
.
2010 Dec 30
;
363
(
27
):
2628
37
. .
14.
Fu
X
,
Chen
G
,
Cai
ZD
,
Wang
C
,
Liu
ZZ
,
Lin
ZY
, et al.
Overexpression of BUB1B contributes to progression of prostate cancer and predicts poor outcome in patients with prostate cancer
.
Onco Targets Ther
.
2016
;
9
:
2211
20
. .
15.
Pan
S
,
Zhan
Y
,
Chen
X
,
Wu
B
,
Liu
B
.
Identification of Biomarkers for Controlling Cancer Stem Cell Characteristics in Bladder Cancer by Network Analysis of Transcriptome Data Stemness Indices
.
Front Oncol
.
2019
;
9
:
613
. .
16.
Zhang
Y
,
Tseng
JT
,
Lien
IC
,
Li
F
,
Wu
W
,
Li
H
.
mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers
.
Genes (Basel)
.
2020 Feb 27
(
3
):
11
.
17.
Wei
W
,
Lv
Y
,
Gan
Z
,
Zhang
Y
,
Han
X
,
Xu
Z
.
Identification of key genes involved in the metastasis of clear cell renal cell carcinoma
.
Oncol Lett
.
2019 May
;
17
(
5
):
4321
8
. .
18.
Xu
D
,
Xu
Y
,
Lv
Y
,
Wu
F
,
Liu
Y
,
Zhu
M
, et al.
Identification of Four Pathological Stage-Relevant Genes in Association with Progression and Prognosis in Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis
.
Biomed Res Int
.
2020
;
2020
:
2137319
. .
19.
Sekino
Y
,
Han
X
,
Babasaki
T
,
Goto
K
,
Inoue
S
,
Hayashi
T
, et al.
Microtubule-associated protein tau (MAPT) promotes bicalutamide resistance and is associated with survival in prostate cancer
. Urol Oncol. 2020 Oct;38(10):795.e1–795.e8.
20.
Tang
Z
,
Li
C
,
Kang
B
,
Gao
G
,
Li
C
,
Zhang
Z
.
GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses
.
Nucleic Acids Res
.
2017 Jul 3
;
45
(
W1
):
W98
W102
. .
21.
Wozniak
MB
,
Le Calvez-Kelm
F
,
Abedi-Ardekani
B
,
Byrnes
G
,
Durand
G
,
Carreira
C
, et al.
Integrative genome-wide gene expression profiling of clear cell renal cell carcinoma in Czech Republic and in the United States
.
PLoS One
.
2013
;
8
(
3
):
e57886
. .
22.
Wotschofsky
Z
,
Gummlich
L
,
Liep
J
,
Stephan
C
,
Kilic
E
,
Jung
K
, et al.
Integrated microRNA and mRNA Signature Associated with the Transition from the Locally Confined to the Metastasized Clear Cell Renal Cell Carcinoma Exemplified by miR-146-5p
.
PLoS One
.
2016
;
11
(
2
):
e0148746
. .
23.
Ascierto
ML
,
McMiller
TL
,
Berger
AE
,
Danilova
L
,
Anders
RA
,
Netto
GJ
, et al.
The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti-PD-1 Response in Patients with Renal Cell Carcinoma
.
Cancer Immunol Res
.
2016 Sep 2
;
4
(
9
):
726
33
. .
24.
Nam
HY
,
Chandrashekar
DS
,
Kundu
A
,
Shelar
S
,
Kho
EY
,
Sonpavde
G
, et al.
Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis
.
Mol Cancer Res
.
2019 Jan
;
17
(
1
):
84
96
. .
25.
Zhao
Q
,
Xue
J
,
Hong
B
,
Qian
W
,
Liu
T
,
Fan
B
, et al.
Transcriptomic characterization and innovative molecular classification of clear cell renal cell carcinoma in the Chinese population.
Cancer Cell Int
.
2020
;
20
:
461
.
26.
Calinawan
AP
,
Song
X
,
Ji
J
,
Dhanasekaran
SM
,
Petralia
F
,
Wang
P
, et al.
ProTrack: An Interactive Multi-Omics Data Browser for Proteogenomic Studies
.
Proteomics
.
2020 Jun 8
:
e1900359
. .
27.
Li
T
,
Fu
J
,
Zeng
Z
,
Cohen
D
,
Li
J
,
Chen
Q
, et al.
TIMER2.0 for analysis of tumor-infiltrating immune cells
.
Nucleic Acids Res
.
2020 Jul 2
;
48
(
W1
):
W509
W514
. .
28.
Clark
DJ
,
Dhanasekaran
SM
,
Petralia
F
,
Pan
J
,
Song
X
,
Hu
Y
, et al.
Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma
.
Cell
.
2019 Oct 31
;
179
(
4
):
964
–983.
e31
. .
29.
Goldman
MJ
,
Craft
B
,
Hastie
M
,
Repečka
K
,
McDade
F
,
Kamath
A
, et al.
Visualizing and interpreting cancer genomics data via the Xena platform
.
Nat Biotechnol
.
2020 Jun
;
38
(
6
):
675
8
. .
30.
Brodaczewska
KK
,
Szczylik
C
,
Fiedorowicz
M
,
Porta
C
,
Czarnecka
AM
.
Choosing the right cell line for renal cell cancer research
.
Mol Cancer
.
2016 Dec 19
;
15
(
1
):
83
. .
31.
Sukach
AN
,
Ivanov
EN
.
[Formation of spherical colonies as a property of stem cells]
.
Tsitologiia
.
2007
;
49
(
11
):
916
22
.
32.
Yamamoto
Y
,
Oga
A
,
Akao
J
,
Misumi
T
,
Fuji
N
,
Kobayashi
K
, et al.
BUBR1 overexpression predicts disease-specific survival after nephroureterectomy in patients with upper tract urothelial carcinoma
.
Jpn J Clin Oncol
.
2016 Aug
;
46
(
8
):
754
61
. .
33.
Zhao
Y
,
Ando
K
,
Oki
E
,
Ikawa-Yoshida
A
,
Ida
S
,
Kimura
Y
, et al.
Aberrations of BUBR1 and TP53 gene mutually associated with chromosomal instability in human colorectal cancer
.
Anticancer Res
.
2014 Oct
;
34
(
10
):
5421
7
.
34.
Finlay
CA
,
Hinds
PW
,
Tan
TH
,
Eliyahu
D
,
Oren
M
,
Levine
AJ
.
Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life
.
Mol Cell Biol
.
1988 Feb
;
8
(
2
):
531
9
. .
35.
Li
M
,
Fang
X
,
Baker
DJ
,
Guo
L
,
Gao
X
,
Wei
Z
, et al.
The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis
.
Proc Natl Acad Sci USA
.
2010 Aug 10
;
107
(
32
):
14188
93
. .
36.
Tang
Z
,
Kang
B
,
Li
C
,
Chen
T
,
Zhang
Z
.
GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis
.
Nucleic Acids Res
.
2019 Jul 2
;
47
(
W1
):
W556
60
. .
37.
Ayers
M
,
Lunceford
J
,
Nebozhyn
M
,
Murphy
E
,
Loboda
A
,
Kaufman
DR
, et al.
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade
.
J Clin Invest
.
2017 Aug 1
;
127
(
8
):
2930
40
. .
38.
Hanze
J
,
Wegner
M
,
Noessner
E
,
Hofmann
R
,
Hegele
A
.
Co-Regulation of Immune Checkpoint PD-L1 with Interferon-Gamma Signaling is Associated with a Survival Benefit in Renal Cell Cancer
.
Target Oncol
.
2020 Jun
;
15
(
3
):
377
90
.
39.
Wang
X
,
Sun
Q
.
TP53 mutations, expression and interaction networks in human cancers
.
Oncotarget
.
2017 Jan 3
;
8
(
1
):
624
43
. .
40.
Donehower
LA
,
Soussi
T
,
Korkut
A
,
Liu
Y
,
Schultz
A
,
Cardenas
M
, et al.
Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas
.
Cell Rep
.
2019 Jul 30
;
28
(
5
):
1370
–1384.
e5
. .
41.
Scintu
M
,
Vitale
R
,
Prencipe
M
,
Gallo
AP
,
Bonghi
L
,
Valori
VM
, et al.
Genomic instability and increased expression of BUB1B and MAD2L1 genes in ductal breast carcinoma
.
Cancer Lett
.
2007 Sep 8
;
254
(
2
):
298
307
. .
42.
Baker
DJ
,
Dawlaty
MM
,
Wijshake
T
,
Jeganathan
KB
,
Malureanu
L
,
van Ree
JH
, et al.
Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan
.
Nat Cell Biol
.
2013 Jan
;
15
(
1
):
96
102
. .
43.
Weaver
RL
,
Limzerwala
JF
,
Naylor
RM
,
Jeganathan
KB
,
Baker
DJ
,
van Deursen
JM
.
BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer
.
Elife
.
2016 Aug 16
;
5
:
5
. .
44.
Xu
W
,
Atkins
MB
,
McDermott
DF
.
Checkpoint inhibitor immunotherapy in kidney cancer
.
Nat Rev Urol
.
2020 Mar
;
17
(
3
):
137
50
. .
45.
Shevtsov
M
,
Sato
H
,
Multhoff
G
,
Shibata
A
.
Novel Approaches to Improve the Efficacy of Immuno-Radiotherapy
.
Front Oncol
.
2019
;
9
:
156
. .
46.
Ma
Q
,
Liu
Y
,
Shang
L
,
Yu
J
,
Qu
Q
.
The FOXM1/BUB1B signaling pathway is essential for the tumorigenicity and radioresistance of glioblastoma
.
Oncol Rep
.
2017 Dec
;
38
(
6
):
3367
75
. .
47.
Xue
YJ
,
Xiao
RH
,
Long
DZ
,
Zou
XF
,
Wang
XN
,
Zhang
GX
, et al.
Overexpression of FoxM1 is associated with tumor progression in patients with clear cell renal cell carcinoma
.
J Transl Med
.
2012 Sep 24
;
10
:
200
. .
48.
Song
J
,
Song
F
,
Liu
K
,
Zhang
W
,
Luo
R
,
Tang
Y
, et al.
Multi-omics analysis reveals epithelial-mesenchymal transition-related gene FOXM1 as a novel prognostic biomarker in clear cell renal carcinoma
.
Aging (Albany NY)
.
2019 Nov 19
;
11
(
22
):
10316
37
. .
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