The Circadian Gene NPAS2 Act as a Putative Tumor Stimulative Factor for Uterine Corpus Endometrial Carcinoma

Abstract

Background: Mounting evidence indicates altered circadian rhythm represents a critical factor affecting carcinogenesis and tumor progression. The circadian gene neuronal PAS domain protein 2 (NPAS2) constitutes a newly discovered prognostic biomarker. NPAS2 dysregulation is found in multiple malignancies, although its functions in uterine corpus endometrial carcinoma (UCEC) remain largely unknown. Objective: To evaluate NPAS2's roles in UCEC and to explore the underlying mechanisms. Methods: NPAS2 transcription levels, patient prognosis, different clinical stages and target microRNAs in UCEC cases were comparatively assessed based on public databases, including UALCAN, GEPIA, TIMER, Kaplan-Meier plotter, starBase database, LinkedOmics and String. Then, qRT-PCR and immunohistochemical analysis were applied to analyze the expression of NPAS2 in UCEC tissue samples. CCK-8, clonogenic assay and flow cytometry were carried out for detecting cell viability, colony formation ability and cell apoptosis, respectively. Results: NPAS2 was upregulated in tissue samples from UCEC cases compared with the corresponding control specimens. NPAS2 overexpression was associated with decreased overall (OS), disease free (DFS) and relapse free (RFS) survival in UCEC. In addition, NPAS2 overexpression was associated with clinical stage, tumor grade, estrogen receptor status, myometrial invasion in UCEC. Furthermore, NPAS2 knockdown or overexpression altered cell proliferation and apoptosis in UCEC. Moreover, NPAS2 showed significant negative correlations with miR-17-5p and miR-93-5p, and positive correlations with miR-106a-5p and miR-381-3p in UCEC. Conclusion: NPAS2 overexpression is associated with poor prognosis and clinicopathological characteristics in UCEC and promotes proliferation and colony formation while inhibiting apoptosis. Finally, NPAS2 is associated with several miRNAs in UCEC.

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids

“…Zhao et al indicated that miR-381-3p overexpression could accelerate cell proliferation and colony formation, which further initiates renal tumor deterioration and poor prognosis ( Zhao et al, 2020 ). A gynecologic cancer-associated study also elucidated that miR-381-3p had a positive correlation with uterine corpus endometrial carcinoma ( Zheng et al, 2021 ). Furthermore, some studies showed that miR-381-3p was upregulated in glioma ( Li et al, 2016 ), osteosarcoma ( Li et al, 2016 ), synovial sarcoma ( Hisaoka et al, 2011 ) and epithelioid sarcoma ( Papp et al, 2014 ).…”

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

“…The dysregulation of the BMAL1/NPAS2 heterodimer is associated with high levels of the c-Myc gene in cells, leading to genomic instability and an increase in tumorigenesis [ 131 , 132 , 133 , 134 ]. Thus, the overexpression of NPAS2 is present in different types of cancer, indicating that the same mechanism could also occur in leukemia [ 135 , 136 , 137 , 138 ].…”

The Expression of Pyroptosis-Related Gene May Influence the Occurrence, Development, and Prognosis of Uterine Corpus Endometrial Carcinoma

“…Yu et al (29) found that g-glutamyl hydrolase (GGH) expression levels were associated with Th2 cell expression and low-killer cell infiltration of CD56 bright cells, a process that could drive UCEC progression. Zheng et al (30) found that NPAS2 could lead to UCEC via an increase in tumor immune cell infiltration. Liu et al (31) developed and validated a Treg-related risk signature (TRRS) to assess the prognosis of UCEC and reflect the immune status of UCEC; this TRRS was capable of predicting the prognosis of UCEC patients that allowed for personalized treatment to be provided.…”