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Isoliquiritigenin reduces brain metastasis by circNAV3-ST6GALNAC5-EGFR axis in triple-negative breast cancer
Yi Xie1, Jindong Xie1, Guoxian Huang1
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
Abstract:
Brain metastasis (BM) is a serious complication of increasing incidence in patients with advanced breast cancer, which is characterized by swift deterioration in quality of life with few efficient therapy strategies. There is an urgent clinical requirement to devise potent therapeutic strategies for the prevention and management of brain metastases. Here, we report isoliquiritigenin (ISL), a key bioactive substance extracted from licorice root, which effectively inhibited triple-negative breast cancer (TNBC) brain metastasis (BM) by downregulation of circNAV3. CircRNAs expression analyses and functional studies, coupled with clinical significance investigations identified circNAV3 as a key molecule promoting TNBC BM. Functionally, circNAV3 could promote proliferation, migration, invasion, angiogenesis and capacity to penetrate the blood-brain barrier of TNBC cells. Mechanistically, circNAV3 could competitively bind with miR-4262, hence intercepting the suppressive effect of miR-4262 on ST6GALNAC5. Subsequently, this interplay enhanced EGFR sialylation and activation, initiating the PI3K/Akt pathway and ultimately fostering the development of TNBC brain metastases. In conclusion, our research establishes that ISL impede the initiation and advancement of TNBC brain metastasis by modulation of circNAV3/miR-4262/ST6GALNAC5/EGFR axis, laying a theoretical groundwork for the therapeutic use of ISL in this scenario.
Insights
Isoliquiritigenin (ISL) inhibits triple-negative breast cancer brain metastasis by targeting circNAV3. This research provides a new therapeutic strategy for preventing and managing brain metastases in advanced breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Brain metastasis (BM) is a severe complication in advanced breast cancer, significantly impacting patient quality of life.
- Current therapeutic strategies for TNBC brain metastasis are limited, highlighting an urgent need for novel treatments.
Purpose of the Study:
- To investigate the inhibitory effect of isoliquiritigenin (ISL) on triple-negative breast cancer (TNBC) brain metastasis.
- To elucidate the molecular mechanisms underlying ISL's action, focusing on the circNAV3/miR-4262/ST6GALNAC5/EGFR signaling axis.
Main Methods:
- CircRNA expression analysis and functional studies in TNBC models.
- Investigation of the interaction between circNAV3, miR-4262, and ST6GALNAC5.
- Assessment of ISL's efficacy in preclinical models of TNBC brain metastasis.
Main Results:
- circNAV3 was identified as a key promoter of TNBC brain metastasis, enhancing proliferation, migration, invasion, and blood-brain barrier penetration.
- ISL effectively inhibited TNBC brain metastasis by downregulating circNAV3.
- The mechanism involves circNAV3 competitively binding miR-4262, relieving its suppression of ST6GALNAC5, leading to enhanced EGFR sialylation and PI3K/Akt pathway activation.
Conclusions:
- ISL demonstrates potent inhibitory effects against TNBC brain metastasis through the circNAV3/miR-4262/ST6GALNAC5/EGFR pathway.
- This study provides a strong theoretical basis for the clinical application of ISL in treating and preventing TNBC brain metastasis.
