Key Takeaways & Executive Findings
- •• KLF7 is overexpressed in cervical cancer tissues and correlates with poor patient survival, acting as an oncogene. • KLF7 promotes cervical cancer cell proliferation, migration, invasion, and metabolic reprogramming by modulating key genes like PFKL and ACADL. • Knockout of KLF7 Exon 2 paradoxically increases nuclear KLF7 and oncogenic potential, highlighting complex regulatory mechanisms. • Alpha-lipoic acid (ALA) downregulates KLF7 expression and suppresses cervical cancer progression, suggesting a potential therapeutic strategy.
Abstract
It is unclear what part KLF7 plays in cervical cancer. In this study, immunohistochemical and bioinformatics analyses reveal that KLF7 expression is lower in normal cervical tissues than in cervical cancer tissues, and the high level of KLF7 transcripts in cervical cancer tissues is negatively correlated with patients’ overall and disease-free survival. In addition, KLF7 overexpression facilitates the proliferation, migration, and invasion of cervical cells, reduces PFKL expression, and increases the expressions of KLF4, Nanog, OCT4, CD44, SOX2, and ACADL. Additionally, knocking out the Exon 2 of KLF7 in HeLa cells results in a decrease in the total expression of KLF7 but an increase in the nuclear expression of KLF7, an increase in the capacity for proliferation, migration, invasion, and oncogenicity, and an increase in the density and ridge density of mitochondria. Consistent with these findings, RNA-seq analysis shows that knocking out the Exon 2 of KLF7 facilitates the expression of gene sets associated with cancer compared with that in wild-type HeLa cells. Moreover, the administration of alpha-lipoic acid (ALA) leads to a reduction in KLF7 expression in cells and tumor tissues, a suppression of the proliferation, migration, and invasion of HeLa and SiHa cells, and an increase in the carcinogenic potential of HeLa cells, while KLF7 overexpression shows the opposite effect on the expressions of ACADL and PFKL in HeLa and SiHa cells. In conclusion, KLF7 promotes the development of cervical cancer, and ALA can downregulate KLF7 expression and play a positive role in cervical cancer treatment.
1. Introduction
Cervical cancer is the fourth most common cancer among females and is associated with high morbidity and mortality worldwide [1,2]. There were approximately 604,127 newly reported cases of cervical cancer, and more than 342,000 deaths resulted from cervical cancer globally in 2020. Approximately 18% of the cases and 17% of the deaths were from China [3]. Surgery and radiation therapy are effective methods for the clinical treatment of cervical cancer; however, more treatment methods and drugs are still needed to improve the cure rate of patients to date [4].
The development of new treatment methods or drugs requires understanding the molecular mechanisms of cervical cancer development as much as possible. Infection with human papilloma virus (HPV) is a necessary condition for the occurrence of cervical cancer [5–7]. However, HPV infection does not always lead to cervical cancer [8]. The alteration of gene transcription patterns in cervical epithelial cells is the real reason for the development of cervical cancer, in which transcription factors play key roles [9]. In addition, increased metabolic capacity and metabolic pattern reprogramming in cancer cells are important hallmarks of carcinogenesis [10].
Krüppel-like factor 7 (KLF7) is a ubiquitously expressed zinc-finger transcription factor that regulates the development of the nervous system, adipose tissue, and type 2 diabetes, as well as the maintenance of stem cells [11]. In addition, KLF7 acts as an oncogene, and its expression is upregulated in various cancer tissues, including liver cancer, lung cancer, gastric cancer, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, glioma, and ovarian cancer [12,13]. Recent studies have suggested that KLF7 potentially plays a crucial role in regulating the cellular inclination toward glucose and fatty acid metabolism [14]. Tumor cells undergo metabolic reprogramming as a means of adapting to hypoxia and nutritional shortages. The regulation of glucose and fatty acid metabolism by KLF7 might contribute to metabolic reprogramming in cancer cells. In addition, the biological function of KLF7 in cervical cancer development is not clear. In this study, the role of KLF7 in the development of cervical cancer was investigated, and the results revealed that KLF7 is an oncogene of cervical cancer and that alpha-lipoic acid (ALA) inhibits cervical cancer development at least by inhibiting KLF7 transcription.
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Yi Mao, Hongtao Li, Gang Xu, Jiazhen Tian, Yuechan Chen, Zhiwei Zhang (2026). Alpha-lipoic acid targets KLF7 expression to inhibit cervical cancer progression. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024212
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Frequently Asked Questions
What is the role of KLF7 in cervical cancer?
KLF7 acts as an oncogene in cervical cancer, promoting proliferation, migration, invasion, and metabolic reprogramming. Its high expression is associated with poor patient survival.
How does alpha-lipoic acid affect cervical cancer cells?
Alpha-lipoic acid (ALA) downregulates KLF7 expression, thereby suppressing cervical cancer cell proliferation, migration, and invasion, and reducing tumorigenic potential.
What is the significance of KLF7 Exon 2 knockout?
Knocking out Exon 2 of KLF7 reduces total KLF7 expression but increases nuclear KLF7, paradoxically enhancing oncogenic properties and mitochondrial density, indicating complex regulatory mechanisms.
What genes are modulated by KLF7 in cervical cancer?
KLF7 overexpression reduces PFKL expression and increases KLF4, Nanog, OCT4, CD44, SOX2, and ACADL, which are involved in stemness and metabolic reprogramming.
Could alpha-lipoic acid be a potential therapeutic agent for cervical cancer?
Yes, ALA shows promise as a therapeutic agent by targeting KLF7 and inhibiting cervical cancer progression, warranting further clinical investigation.
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