Abstract
ObjectiveOvarian cancer (OV) is the most fatal and frequent type of gynecological malignancy worldwide. TIMELESS (TIM), as a circadian clock gene, has been found to be highly expressed and predictive of poor prognosis in various cancers. However, the function of TIM in OV is not known. This study was designed to investigate the biological functions and underlying mechanisms of TIM during OV progression.MethodsCell viability assay, cell migration assay, immunohistochemistry staining, qPCR analyses, and tumor xenograft model were used to identify the functions of TIM in OV. Bioinformatics analyses, including GEPIA, cBioPortal, GeneMANIA, and TIMER, were used to analyze the gene expression, genetic alteration, and immune cell infiltration of TIM in OV.ResultsTIM is highly expressed in OV patients. TIM knockdown inhibited OV cell proliferation, migration, and invasion both in vitro and in vivo. Genetic alteration of TIM was identified in patients with OV. TIM co-expression network indicates that TIM had a wide effect on the immune cell infiltration and activation in OV. Further analysis and experimental verification revealed that TIM was positively correlated with macrophages infiltration in OV.ConclusionsOur study unveiled a novel function of highly expressed TIM associated with immune cell especially macrophages infiltration in OV. TIM may serve as a potential prognostic biomarker and immunotherapy target for OV patients.
Highlights
Ovarian cancer (OV) is the second leading cause of gynecologic cancer-related death in women around the world [1]
TIM mRNA expression was significantly upregulated in ovarian cancer (OV) tissues compared to normal ovarian epithelial tissues (Figure 1A)
As macrophages have the best correlation with TIM expression level in OV (Supplementary Figure 3A), we focused on the macrophages and checked the macrophage infiltration by using the OV tissue microarray
Summary
Ovarian cancer (OV) is the second leading cause of gynecologic cancer-related death in women around the world [1]. More and more epidemiological evidences have suggested that a disturbed circadian rhythm was positively correlated with the risk of health disorders, such as obesity, cardiovascular disease, and cancer [4, 5]. Biorhythms are essential for maintaining the whole-body homeostasis, while the disruption of biorhythms can cause the dysregulation of homeostasis and accelerate the development of diseases [6,7,8]. Circadian rhythm disruption can contribute to suppress melatonin, which is a neurohormone known for its role in hindering cancer initiation and progression [9,10,11]. The mechanisms for the circadian rhythm in cancer are not well elucidated. One study has pointed out that circadian disruption led to circadian dysregulation of DNA repair genes and increased DNA damage and potentially elevated cancer risk [14]
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