Abstract
The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.
Highlights
Among Chinese women aged 15–44 years, cervical cancer is the second most common cancer and the most common gynecological malignancy (Liou et al, 2016; Gu et al, 2017; Vu et al, 2018)
We examined the effect of Fra-1 overexpression on the cell cycle distribution of HeLa cells by flow cytometry and found that the percentage of cells in S phase was 13.32% among Fra-1–overexpressing HeLa cells, which was lower than that of 24.57% among the control cells (Figure 1D)
The results showed that the proportion of early apoptotic cells among the Fra-1–overexpressing HeLa cells was 6.01%, while that in the control group was only 2.99% (Figure 1E)
Summary
Among Chinese women aged 15–44 years, cervical cancer is the second most common cancer and the most common gynecological malignancy (Liou et al, 2016; Gu et al, 2017; Vu et al, 2018). The incidence of cervical cancer in younger patients has increased. The incubation period for HPV is long, with oncogenesis commonly occurring 8–10 years after infection. While HPV infection is a known cause of cervical cancer, it does not fully explain the occurrence of cervical cancer. Other factors are important in the malignant transformation of highgrade HPV infection (Kaliff et al, 2018; Farazi et al, 2019; So et al, 2019). Many gaps in knowledge regarding cervical cancer pathogenesis and the corresponding treatment mechanism remain to be filled
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