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Circ-ERBB2 knockdown sensitized colorectal cancer cells to 5-FU via miR-181a-5p/PTEN/Akt pathway
Yueli Zhang1, Xinchun Wang2, Shuyun Wang2
1Department of Clinical Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China.
Abstract:
Colorectal cancer (CRC) is the fourth most deadly cancer worldwide, drug resistance impedes treatment of CRC. It is still urgent to find new molecular targets to improve the sensitivity of chemotherapeutic drugs. In this study, circ-ERBB2 was upregulated in CRC cells. Upregulation of circ-ERBB2 promoted CRC cells proliferation and clone formation, but inhibited apoptosis. We identified miR-181a-5p as circ-ERBB2's target. The effect of miR-181a-5p on CRC cells was contrary to circ-ERBB2, miR-181a-5p downregulation abolished the function of circ-ERBB2 silencing in CRC cells. In addition, phosphatase and tensin homolog (PTEN) was verified as miR-181a-5p's downstream target, circ-ERBB2 activates the Akt pathway and inhibits cell apoptosis through modulating miR-181a-5p/PTEN. Circ-ERBB2 silencing significantly reduced CRC cell resistance to 5-FU. miR-181a-5p downregulation abolished the role of circ-ERBB2 knockdown in CRC cell resistance to 5-FU. In conclusion, upregulation of circ-ERBB2 promoted the malignancy of CRC and reduced CRC cell resistance to 5-FU. Besides, additional mechanism study provided a novel regulatory pathways that circ-ERBB2 knockdown promoted CRC cell sensitivity to 5-FU by regulating miR-181a-5p/PTEN/Akt pathway. This research indicated that circ-ERBB2 may be a valuable biomarker for the diagnosis and treatment of CRC.
Insights
Circular RNA circ-ERBB2 promotes colorectal cancer (CRC) malignancy and 5-FU drug resistance. Silencing circ-ERBB2 enhances CRC sensitivity to 5-FU by regulating the miR-181a-5p/PTEN/Akt pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) is a leading cause of cancer death globally.
- Drug resistance remains a significant challenge in CRC treatment.
- Novel molecular targets are needed to improve chemotherapeutic drug sensitivity.
Purpose of the Study:
- To investigate the role of circ-ERBB2 in colorectal cancer progression and chemoresistance.
- To elucidate the regulatory pathway involving circ-ERBB2, miR-181a-5p, and PTEN in CRC.
- To assess the potential of circ-ERBB2 as a biomarker for CRC diagnosis and treatment.
Main Methods:
- Quantitative real-time PCR to measure circ-ERBB2 and miR-181a-5p expression.
- Cell proliferation, clone formation, and apoptosis assays.
- Western blotting to detect PTEN and Akt pathway proteins.
- 5-Fluorouracil (5-FU) resistance assays.
Main Results:
- Circ-ERBB2 was upregulated in CRC cells and promoted proliferation while inhibiting apoptosis.
- Circ-ERBB2 targeted miR-181a-5p, which in turn targeted PTEN, activating the Akt pathway.
- Circ-ERBB2 upregulation reduced CRC cell sensitivity to 5-FU.
- Silencing circ-ERBB2 re-sensitized CRC cells to 5-FU by modulating the miR-181a-5p/PTEN/Akt pathway.
Conclusions:
- Circ-ERBB2 promotes colorectal cancer malignancy and chemoresistance.
- The circ-ERBB2/miR-181a-5p/PTEN/Akt axis represents a novel regulatory pathway in CRC.
- Circ-ERBB2 is a potential diagnostic and therapeutic target for improving CRC treatment outcomes.
