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Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.

ABSTRACT: Autophagy plays a key role in colorectal cancer (CRC) development and reduces the sensitivity of CRC cells to treatment. The present study reported a novel tumor?suppressive role for autophagy, which was demonstrated to be regulated through the novel oncogene neurotrophin?4 (NTF4). NTF4 was significantly overexpressed in tumor tissue compared with non?tumor mucosa, and the upregulation of NTF4 in CRC was associated with poor overall survival and advanced TNM stage. The genetic knockdown of NTF4 using short hairpin RNA in CRC cells prevented epithelial?to?mesenchymal transition and activated autophagy; this was regulated through the interaction between autophagy?associated gene 5 (Atg5) and the mitogen?activated protein kinase pathway. In addition, the knockdown of NTF4 inhibited cell invasion, migration, proliferation and colony formation, and promoted cell cycle arrest. Treatment of the cells with the autophagy inhibitor chloroquine (CQ) rescued these functions and promoted cell invasion, migration, proliferation and colony formation. Finally, the knockdown of NTF4 inhibited the growth of subcutaneous xenografts in Balb/c?nu mice. In conclusion, these findings suggested that NTF4 may be a diagnostic marker associated with the overall survival and progression of patients with CRC. NTF4 was found to promote tumorigenesis and CRC development through autophagy regulation.

SUBMITTER: Yang Z

PROVIDER: S-EPMC7170041 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.

Yang Zhou Z Chen Yusheng Y Wei Xiyi X Wu Dejun D Min Zhijun Z Quan Yingjun Y

International journal of oncology 20200326 6

Autophagy plays a key role in colorectal cancer (CRC) development and reduces the sensitivity of CRC cells to treatment. The present study reported a novel tumor‑suppressive role for autophagy, which was demonstrated to be regulated through the novel oncogene neurotrophin‑4 (NTF4). NTF4 was significantly overexpressed in tumor tissue compared with non‑tumor mucosa, and the upregulation of NTF4 in CRC was associated with poor overall survival and advanced TNM stage. The genetic knockdown of NTF4 ...[more]

PMID: 32236587

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Project description:Background: The programmed cell death 1 (PD-1) receptor is an immune checkpoint molecule that induces immune tolerance and mediates the immune escape of tumor cells. It is mainly expressed in immune cells such as T cells, B cells and monocytes. In recent years, studies have shown that tumor cell-intrinsic PD-1 plays different roles in the development of melanoma, Liver cancer and lung cancer. However, the expression and function of PD-1 in colon cancer cells has not been reported. Our previous studies have found that Candida tropicalis (C. tropicalis) can promote CRC tumor growth and chemotherapy resistance to oxaliplatin by regulating mismatch repair system. Whether C. tropicalis participates in the progression of CRC and immunotherapy resistance through regulating the tumor cell-intrinsic PD-1 remains to be further elucidated. Methods & Results: In this study, we first found that high concentrations of C. tropicalis promote tumor growth in cell cultures and xenografts. In addition, we proved that colon cancer cell lines express PD-1 receptors. Knockdown of PD-1 enhanced SW480 viability in-vitro, while overexpression of PD-1 diminished cell viability. Moreover, blocking antibody against PD-1 promotes tumor growth both in SW480 cells and mice CRC xenografts in an adaptive immune-independent manner. We also demonstrated that high concentrations of C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression in colon cancer cells. CRC cell growth induced by C. tropicalis is partially offset in the presence of PD-1 overexpression. This shows that C. tropicalis promotes CRC progression via controlling the expression of tumor cell-intrinsic PD-1. Mechanistically, we found that C. tropicalis modulates the expression of PD-1 via increasing the autophagy traffic in colon cancer cells. Combining autophagy inhibitor with C. tropicalis treatment partly blocked the CRC tumor growth and reversed the downregulation of PD-1. Conclusion: This study shows that PD-1 is a tumor suppressor in CRC. C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression via enhancing tumor cells autophagy levels to promote CRC progression. It may provide a new idea and mechanism for answering why the immune monoclonal antibody treatment is ineffective in cancer patients.

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Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.

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Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.

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