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NudCL2 suppresses pancreatic cancer progression by inhibiting SLC7A11-mediated EMT and metastasis
Jiaxing Feng1, Mingyang Yang1, Rijin Lin1
1Institute of Gastroenterology of the Second Affiliated Hospital, Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Abstract:
Pancreatic cancer (PC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. NudC-like protein 2 (NudCL2), a molecular cochaperone of HSP90, has been implicated in various cellular processes; however, its role in pancreatic cancer remains poorly understood. In this study, we report that NudCL2 expression is significantly downregulated in PC tissues and is correlated with poor patient survival. The results of functional assays revealed that NudCL2 knockdown enhances cell invasion and migration in vitro and promotes lung and liver metastases in vivo. Further analysis revealed solute carrier family 7 member 11 (SLC7A11) as a key downstream effector that was upregulated upon NudCL2 depletion. Suppression of SLC7A11 reversed the increase in cell motility induced by NudCL2 depletion. Mechanistically, our findings suggest that NudCL2 regulates the transcriptional activity of SLC7A11 and that the NudCL2/SLC7A11 axis may suppress cell motility by inhibiting the epithelial-mesenchymal transition (EMT) pathway. Collectively, these results highlight the important role of NudCL2 in PC progression through the modulation of EMT via SLC7A11, providing valuable insights into its potential as both a therapeutic target and a prognostic biomarker.
Insights
NudC-like protein 2 (NudCL2) is downregulated in pancreatic cancer (PC), promoting tumor cell invasion and metastasis. Restoring NudCL2 function, possibly via SLC7A11 regulation, could offer new therapeutic strategies for PC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic cancer (PC) is aggressive with poor prognosis and limited treatments.
- The role of NudC-like protein 2 (NudCL2), an HSP90 cochaperone, in PC is largely unknown.
- Understanding novel molecular mechanisms is crucial for improving PC therapy.
Purpose of the Study:
- Investigate the function and mechanism of NudCL2 in pancreatic cancer progression.
- Determine the relationship between NudCL2 expression and patient survival.
- Identify downstream effectors and pathways regulated by NudCL2 in PC.
Main Methods:
- Analysis of NudCL2 expression in PC tissues and correlation with survival data.
- In vitro cell invasion and migration assays following NudCL2 knockdown.
- In vivo metastasis assays in mouse models.
- Western blotting and gene expression analysis to identify downstream targets.
- Functional rescue experiments by suppressing identified effectors.
Main Results:
- NudCL2 expression is significantly downregulated in PC tissues, correlating with poor survival.
- NudCL2 depletion enhances pancreatic cancer cell invasion, migration, and metastasis.
- Solute carrier family 7 member 11 (SLC7A11) is upregulated upon NudCL2 loss and mediates increased cell motility.
- NudCL2 regulates SLC7A11 transcription, and the NudCL2/SLC7A11 axis inhibits epithelial-mesenchymal transition (EMT).
Conclusions:
- NudCL2 acts as a tumor suppressor in pancreatic cancer.
- The NudCL2/SLC7A11 pathway plays a critical role in suppressing PC cell motility and EMT.
- NudCL2 is a potential prognostic biomarker and therapeutic target for pancreatic cancer.
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