Dataset Information

KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway.

ABSTRACT: BACKGROUND/AIMS:Kinesin family member 20A (KIF20A) is upregulated in multiple cancers and plays important roles in promoting malignant behavior, whereas its exact role in CRC remains unknown. RESULTS:Both genomic and protein expression levels showed that KIF20A was upregulated in CRC. Further functional analyses revealed that KIF20A had a crucial role in improving cell proliferation and resistance to chemotherapy in CRC. Finally, we provided distinct mechanistic evidence that KIF20A achieved all of its pathological functions in CRC by activating the JAK/STAT3 pathway. CONCLUSION:Our results suggested that KIF20A regulated a set of malignant characteristics in CRC by activating the JAK/STAT3 pathway. Our findings indicate a new direction for the development of more effective therapeutic treatments for CRC. METHODS:Three Gene Expression Omnibus datasets and The Cancer Genome Atlas datasets were used to investigate the expression level of KIF20A in CRC. Further experiments included immunohistochemical staining, western blot analysis, qRT-PCR, gene silencing, and a cell-injected xenograft mouse model to investigate the interaction between KIF20A and the JAK/STAT3 signaling pathway in both patient-derived specimens and CRC cell lines.

SUBMITTER: Xiong M

PROVIDER: S-EPMC6949076 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway.

Xiong Man M Zhuang Kangmin K Luo Yunchen Y Lai Qiuhua Q Luo Xiaobei X Fang Yuxin Y Zhang Yue Y Li Aimin A Liu Side S

Aging 20191216 24

<h4>Background/aims</h4>Kinesin family member 20A (KIF20A) is upregulated in multiple cancers and plays important roles in promoting malignant behavior, whereas its exact role in CRC remains unknown.<h4>Results</h4>Both genomic and protein expression levels showed that KIF20A was upregulated in CRC. Further functional analyses revealed that KIF20A had a crucial role in improving cell proliferation and resistance to chemotherapy in CRC. Finally, we provided distinct mechanistic evidence that KIF2 ...[more]

PMID: 31841120

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Project description:Highlights • Enhanced PYCR1 expression had certain clinical value in lung cancer.• PYCR1 might serve as a marker for the diagnosis and prognosis of lung cancer.• PYCR1 promotes the development of lung cancer through JAK-STAT3 pathway.• PYCR1 promotes the expression of PD-L1 in lung cancer.• PYCR1 significantly participated in process of lung cancer progression via the metabolism link between proline and glutamine.• PYCR1 might be a novel therapeutic target for lung cancer. Background Lung cancer is a serious threat to human life. It is of great significance to elucidate the pathogenesis of lung cancer and search for new markers. This study evaluate the clinical value of pyrroline-5-carboxylate reductase 1 (PYCR1) and explore its role and mechanisms in the malignant progression of lung cancer. Methods PYCR1 expression and its relationship with prognosis were analyzed using a bioinformatics database. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were utilized to examine the expression of PYCR1 in lung cancer tissues and peripheral blood. PYCR1-overexpressing lung cancer cells were constructed, then the cell proliferative, migration, and invasion ability was examined by the MTT and Transwell assays. siRNA against PRODH and STAT3 inhibitor sttatic was used to further elucidate the underlying mechanisms. Luciferase and CHIP assays were carried out for validate the how PYCR1 regulated PD-L1 expression via STAT3. Xenograft experiment was performed to determine the role of PYCR1 in vivo. Results Database analysis showed that PYCR1 expression was significantly increased in lung cancer tissues, and its high expression predicted poor prognosis. Lung cancer tissue and peripheral blood of patients showed obviously increased PYCR1 expression, and the sensitivity and specificity of serum PYCR1 in the diagnosis of lung cancer were 75.7% and 60%, respectively. PYCR1 overexpression enhanced the proliferative, migration, and invasion abilities of lung cancer cells. Both PRODH silence and stattic effectively attenuated the function of PYCR1. Animal experiment and IHC data indicated that PYCR1 could activated STAT3 phosphorylation and PD-L1, as well as suppressed T cell infiltration in lung cancer. Finally, we also validated that PYCR1 promoted PD-L1 transcription by elevating STAT3 binding to the gene promoter. Conclusion PYCR1 has certain value in the diagnosis and prognosis of lung cancer. Moreover, through regulating JAK-STAT3 signaling pathway, PYCR1 significantly participated in process of lung cancer progression via the metabolism link between proline and glutamine, indicating that PYCR1 might be also a novel therapeutic target.

Project description:Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Dataset Information

KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway.

Publications

KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway.

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