KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma

Lu, Yingqiang; Qin, Haixiang; Jiang, Bo; Lu, Wei; Hao, Jiange; Cao, Wenmin; Du, Lin; Chen, Wei; Zhao, Xiaozhi; Guo, Hongqian

doi:10.1016/j.canlet.2021.09.014

Cited by 93 publications

(94 citation statements)

References 39 publications

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“…Dysregulation of KLF2 and KLF15 has been reported to play vital roles in a variety of human cancers [ 23 , 24 ]. Consistent with previous study, we demonstrated that KLF2 and KLF15 inhibits breast cancer proliferation and migration [ 25 – 28 ].…”

Section: Discussionmentioning

confidence: 99%

The functions and prognostic value of Krüppel‐like factors in breast cancer

Zhu

Tian

et al. 2022

Cancer Cell Int

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Background Krüppel‐like factors (KLFs) are zinc finger proteins which participate in transcriptional gene regulation. Although increasing evidence indicate that KLFs are involved in carcinogenesis and progression, its clinical significance and biological function in breast cancer are still limited. Methods We investigated all the expression of KLFs (KLF1-18) at transcriptional levels by using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). The mRNA and protein expression levels of KLFs were also determined by using RT-qPCR and immunohistochemistry, respectively. CBioPortal, GeneMANIA and STRING were used to comprehensive analysis of the molecular characteristics of KLFs. The clinical value of prognostic prediction based on the expression of KLFs was determined by using the KM plotter. The relevant molecular pathways of KLFs were further analyzed by using Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Finally, we investigated the effect of KLF2 and KLF15 on biological behavior of breast cancer cells in vitro. Results The expression of KLF2/4/6/8/9/11/15 was significantly down-regulated in breast cancer. The patients with high KLF2, KLF4 or KLF15 expression had a better outcome, while patients with high KLF8 or KLF11 had a poor prognosis. Furthermore, our results showed that KLF2 or KLF15 can be used as a prognostic factor independent on the other KLFs in patients with breast cancer. Overexpression of KLF2 or KLF15 inhibited cell proliferation and migration, and blocked cell cycle at G0/G1 phase, resulting in cell apoptosis. Conclusions KLF2 and KLF15 function as tumor suppressors in breast cancer and are potential biomarkers for prognostic prediction in patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

The functions and prognostic value of Krüppel‐like factors in breast cancer

Zhu

Tian

et al. 2022

Cancer Cell Int

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“…Human ccRCC cell lines 796-O and A498 and human normal kidney cell line HK-2 were cultured in RPMI 1640 medium containing 10% fetal bovine serum as we previously described [ 26 ]. To stimulate ferroptosis in human ccRCC cell lines, 796-O or A498 cells were incubated with erastin (5 μ mol/L) or RSL3 (1 μ mol/L) for 24 h [ 9 ]. To overexpress miR-4735-3p, 796-O or A498 cells were transfected with the miR-4735-3p mimic (50 nmol/L) or mimic control for 6 h using Hieff Trans™ Liposomal Transfection Reagent and then were cultured with fresh medium for an additional 72 h [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…To inhibit endogenous miR-4735-3p, the cells were transfected with the miR-4735-3p inhibitor (100 nmol/L) or inhibitor control [ 26 ]. To clarify the form of cell death in the miR-4735-3p mimic-treated ccRCC cell lines, these cells were incubated with Fer-1 (2 μ mol/L), Lip-1 (1 μ mol/L), DFO (100 μ mol/L), CPX (5 μ mol/L), Nec-1 (2 μ mol/L), Z-VAD (5 μ mol/L), or CQ (25 μ mol/L) for 24 h [ 7 , 9 , 21 ]. To verify the necessity of SLC40A1, 796-O or A498 cells were preinfected with adenovirus carrying full-length human SLC40A1 or Ctrl plasmid at a multiplicity of infection of 10 for 6 h and then incubated in fresh RPMI 1640 medium for 24 h before transfection.…”

Section: Methodsmentioning

confidence: 99%

“…Ferroptosis is a novel form of programmed cell death mainly caused by an iron-dependent accumulation of toxic lipid reactive oxygen species (ROS) and plays critical roles in tumor progression [ 3 – 6 ]. Recent studies have shown that ferroptosis is implicated in the pathogenesis of ccRCC and that targeting ferroptosis provides novel insights to treat human ccRCC [ 7 – 9 ]. Woo et al demonstrated that inducing ferroptosis dramatically decreased the viability of human ccRCC cells [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-4735-3p Facilitates Ferroptosis in Clear Cell Renal Cell Carcinoma by Targeting SLC40A1

Zhu¹,

Song

Chen

et al. 2022

Analytical Cellular Pathology

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Objective. Clear cell renal cell carcinoma (ccRCC) is the major histopathological subtype of renal cancer, and ferroptosis is implicated in the pathogenesis of ccRCC. The present study was aimed at investigating the role and underlying mechanisms of microRNA-4735-3p (miR-4735-3p) in ccRCC. Methods. Human ccRCC cell lines were transfected with the miR-4735-3p mimic or inhibitor to manipulate the expression of miR-4735-3p. Cell proliferation, colony formation, cell migration, cell invasion, cell death, oxidative stress, lipid peroxidation, and iron metabolism were determined. To validate the necessity of solute carrier family 40 member 1 (SLC40A1), human ccRCC cell lines were overexpressed with SLC40A1 using adenoviral vectors. Results. miR-4735-3p expression was reduced in human ccRCC tissues and cell lines but elevated upon ferroptotic stimulation. The miR-4735-3p mimic increased, while the miR-4735-3p inhibitor decreased oxidative stress, lipid peroxidation, iron overload, and ferroptosis of human ccRCC cell lines. Mechanistic studies identified SLC40A1 as a direct target of miR-4735-3p, and SLC40A1 overexpression significantly attenuated iron overload and ferroptosis in the miR-4735-3p mimic-treated human ccRCC cell lines. Conclusion. miR-4735-3p facilitates ferroptosis and tumor suppression in ccRCC by targeting SLC40A1.

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“…Compared to blood composition, lymph fluid has higher levels of glutathione and oleic acid, and less free iron, which can protect cancer cells from decreased oxidative stress and increase their survival in lymph experience. 161 In renal cell carcinoma, KLF2 can impair transcription of glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, inhibiting cancer cell migration and invasion. 162,163 In conclusion, in addition to glucose and lipid metabolism, other metabolites may also participate in the cancer progression.…”

Section: Iron Metabolism and Cancer Metastasismentioning

confidence: 99%

The critical function of metabolic reprogramming in cancer metastasis

Xie

Pan

et al. 2022

Aging and Cancer

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Cancer metastasis is the leading cause of cancer‐related death. It is a complex, inefficient, and multistep process related to poor prognosis and high mortality of patients. Increasing evidence has shown that metabolic programming is a recognized hallmarker of cancer, plays a critical role in cancer metastasis. Metabolism alterations of glucose, lipid, and amino acid provide cancer cells with energy and substances for biosynthesis, maintain biofunctions and significantly affect proliferation, invasion, and metastasis of cancer cells. Tumor microenvironment (TME) is a complex system formed by varieties of cellular and noncellular elements. Nontumor cells in TME also undergo metabolic reprogramming or respond to metabolites to promote migration and invasion of cancer cells. A comprehensive understanding of the regulatory mechanism in metastasis from the metabolic reprogramming aspect is required to develop new therapeutic strategies combatting cancer metastasis. This review illustrates the metabolic reprogramming and interaction of cancer cells and nontumor cells in the TME, and the development of treatment strategies targeting metabolism alterations.

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KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma

Cited by 93 publications

References 39 publications

The functions and prognostic value of Krüppel‐like factors in breast cancer

The functions and prognostic value of Krüppel‐like factors in breast cancer

MicroRNA-4735-3p Facilitates Ferroptosis in Clear Cell Renal Cell Carcinoma by Targeting SLC40A1

The critical function of metabolic reprogramming in cancer metastasis

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