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Published on: January 12, 2020
Multi-omics reveals that NOTCH1 promotes cervical cancer progression and reduces radiosensitivity
Aihua Guo1, Zhixiong Su2, Enhuan Zhang3
1Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
Background:
Cervical cancer is the fourth most common malignancy in women globally. The NOTCH signaling pathway is aberrantly activated in multiple tumors, and NOTCH1, its core transmembrane receptor, is highly expressed in cervical cancer. However, NOTCH1's mechanisms in cervical cancer progression and radiotherapy resistance, as well as its interaction with key molecules, remain unclear.
Methods:
This study explored the role of NOTCH1 in cervical cancer from multi-omics perspectives, including single-cell sequencing, cDNA microarrays, high-throughput sequencing, and immunohistochemistry, combined with a series of in vitro and in vivo experiments.
Results:
NOTCH signaling activity was negatively correlated with the overall survival and recurrence-free survival of cervical cancer patients. As the core molecule of this signaling pathway, NOTCH1 was significantly highly expressed in cervical cancer tissues and promoted cervical cancer cell proliferation in vitro. Single-cell analysis revealed that NOTCH1 was relatively highly expressed in CPA6+ and CEL+ malignant cells and involved in cell cycle regulation; further cell cycle detection assays confirmed that NOTCH1 could promote the G1-S phase transition. In addition, patients with high NOTCH1 expression showed decreased plasma cell infiltration in the microenvironment. Cell communication analysis indicated that malignant cells with high NOTCH1 expression might lead to impaired plasma cell differentiation due to the impairment of the MIF ligand-receptor pathway. Finally, NOTCH1 could reduce the radiosensitivity of cervical cancer cells to radiotherapy both in vitro and in vivo; whereas has-miR-449a, as an upstream regulatory miRNA of NOTCH1, could inhibit cervical cancer cell proliferation and enhance radiosensitivity by inhibiting NOTCH1 expression.
Conclusions:
This study clarifies NOTCH1's role in promoting cervical cancer progression and reducing radiosensitivity, with has-miR-449a as a negative regulator, providing targets for optimizing cervical cancer radiotherapy.
Insights
NOTCH1 promotes cervical cancer progression and reduces radiotherapy sensitivity. has-miR-449a inhibits NOTCH1, offering potential therapeutic targets for cervical cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cervical cancer is a leading global malignancy in women.
- NOTCH1, a key receptor in the NOTCH pathway, is upregulated in cervical cancer.
- The precise role of NOTCH1 in cervical cancer progression and treatment resistance is not fully understood.
Purpose of the Study:
- To investigate the multifaceted role of NOTCH1 in cervical cancer.
- To elucidate NOTCH1's impact on tumor progression, cell cycle regulation, and the tumor microenvironment.
- To explore NOTCH1's influence on radiotherapy resistance and identify potential therapeutic modulators.
Main Methods:
- Multi-omics analysis including single-cell sequencing and cDNA microarrays.
- In vitro and in vivo experimental models of cervical cancer.
- Immunohistochemistry, cell cycle assays, and cell communication analysis.
Main Results:
- NOTCH1 expression negatively correlates with patient survival and promotes cervical cancer cell proliferation by advancing the G1-S phase transition.
- High NOTCH1 expression is linked to reduced plasma cell infiltration and impaired plasma cell differentiation via the MIF pathway.
- NOTCH1 diminishes radiosensitivity in cervical cancer cells, while has-miR-449a inhibits NOTCH1, enhancing radiosensitivity.
Conclusions:
- NOTCH1 drives cervical cancer progression and confers radioresistance.
- has-miR-449a acts as a negative regulator of NOTCH1, suppressing tumor growth and improving radiotherapy outcomes.
- Targeting the NOTCH1 pathway, modulated by has-miR-449a, presents a promising strategy for enhancing cervical cancer radiotherapy.
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