Exploration of prognostic biomarkers and therapeutic targets in the microenvironment of bladder cancer based on CXC chemokines

Xiaoqi Sun; Qunxi Chen; Lihong Zhang; Jiewei Chen; Xinke Zhang; Xiaoqi Sun; Qunxi Chen; Lihong Zhang; Jiewei Chen; Xinke Zhang

doi:10.3934/mbe.2021313

Mathematical Biosciences and Engineering

2021, Volume 18, Issue 5: 6262-6287. doi: 10.3934/mbe.2021313

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Research article

Exploration of prognostic biomarkers and therapeutic targets in the microenvironment of bladder cancer based on CXC chemokines

1.
Department of Urology, Kaiping Central Hospital, Kaiping 529300, China
2.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
3.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

† These authors contributed equally to this work.
Academic Editor: Yang Kuang

Received: 24 May 2021 Accepted: 06 July 2021 Published: 19 July 2021

Background
Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti-tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear.

Methods
We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis.

Results
The mRNA levels of C-X-C motif chemokine ligand (CXCL)1, CXCL5, CXCL6, CXCL7, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and CXCL17 were increased significantly increased, and those of CXCL2, CXCL3, and CXCL12 were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of CXCL1, CXCL6, CXCL10, CXCL11, and CXCL13 mRNA expression are associated significantly with the poor overall survival (all p < 0.05), and similarly, those of CXCL2 and CXCL12 in the TCGA database (p < 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells.

Conclusion
We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.
- bladder cancer,
- biomarkers,
- CXC chemokines,
- microenvironment
Citation: Xiaoqi Sun, Qunxi Chen, Lihong Zhang, Jiewei Chen, Xinke Zhang. Exploration of prognostic biomarkers and therapeutic targets in the microenvironment of bladder cancer based on CXC chemokines[J]. Mathematical Biosciences and Engineering, 2021, 18(5): 6262-6287. doi: 10.3934/mbe.2021313

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Abstract

Background

Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti-tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear.

Methods

We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis.

Results

The mRNA levels of C-X-C motif chemokine ligand (CXCL)1, CXCL5, CXCL6, CXCL7, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and CXCL17 were increased significantly increased, and those of CXCL2, CXCL3, and CXCL12 were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of CXCL1, CXCL6, CXCL10, CXCL11, and CXCL13 mRNA expression are associated significantly with the poor overall survival (all p < 0.05), and similarly, those of CXCL2 and CXCL12 in the TCGA database (p < 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells.

Conclusion

We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.

References

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