ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation

Abstract

BackgroundClinical treatment of RAS mutant cancers is challenging because of the complexity of the Ras signaling pathway. SLC7A5 is a newly discovered downstream gene of the Ras signaling pathway, but the regulatory mechanism is unclear. We aimed to explore the molecular mechanism and role in KRAS mutant lung adenocarcinoma progression.MethodsKey gene that regulated SLC7A5 in KRAS mutant lung adenocarcinoma was screened by RNA sequencing and bioinformatics analysis. The effect of this gene on the expression of SLC7A5 was studied by RNAi. The regulatory mechanism between the two genes was investigated by immunofluorescence, CoIP, pulldown and yeast two-hybrid assays. The location of the two genes was determined by inhibiting Ras and the downstream pathways PI3K-AKT and MEK-ERK. By in vivo and in vitro experiments, the effects of the key gene on the biological functions of KRAS mutant lung adenocarcinoma were explored.ResultsWe found a novel gene, ZNF24, which upregulated SLC7A5 protein expression rather than mRNA expression in KRAS mutant lung adenocarcinoma. Endogenous protein interactions occurred between ZNF24 and SLC7A5. Ras inhibition reduced the expression of ZNF24 and SLC7A5. ZNF24 and SLC7A5 are located downstream of the MEK-ERK and PI3K-AKT pathways. In vivo and in vitro functional experiments confirmed that the ZNF24-SLC7A5 signaling axis promoted the proliferation, invasion and migration of KRAS mutant lung adenocarcinoma.ConclusionsZNF24 promoted the growth of KRAS mutant lung adenocarcinoma by upregulating SLC7A5 protein expression, which suggested that ZNF24 is a new biomarker of KRAS mutant tumors and could be a new potential therapeutic target for Ras-driven tumors.

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“…ZNF24 enhances SLC7A5 expression to promote the growth of KRAS mutant LUAD [ 124 ]. LAT-1 expression was also found to be associated with factors involved in the mTOR pathway (including EGFR, a loss of PTEN, p-mTOR, and p-S6K) and hypoxic situation (including HIF-1α, hexokinase I, VEGF, and CD34) in LUAD [ 125 ].…”

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“…The cell cycle of each group was tested via flow cytometry. The data were analyzed by FlowJo 7.6 (San Carlos, CA, USA) [25].…”

“…The collected cells were resuspended in binding buffer, cultured with Annexin V-FITC (BD Biosciences) for 10 minutes in a dark environment at room temperature and subsequently stained with binding buffer and PI (BD Biosciences) in darkness for 30 minutes at 4 °C. Cell measurement was conducted using flow cytometry [25].…”

“…The migration process was carefully observed at 0, 24 and 48 h on an inverted microscope (Olympus, Tokyo, Japan). Im-ageJ (National institutes of Health, Bethesda, MD, USA) was employed to calculate the migration area [25].…”

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“…KRAS mutations are linked to an unfavorable prognosis and limited responsiveness to standard treatment regimens. [14][15][16][17] the ROS1 gene is altered in about 1-2% of lung cancer patients and generally appears in adenocarcinoma non-small cell lung cancer. ROS1 mutations are predominantly observed in tumors of the adenocarcinoma type that are negative for other driver mutations.…”