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ID2 Inhibits Bladder Cancer Progression and Metastasis via PI3K/AKT Signaling Pathway

ABSTRACT: Background: Inhibitors of DNA-binding (ID) proteins are important regulators of cell proliferation and differentiation. The aim of this study was to evaluated the role of ID proteins in bladder cancer (BCa) and related molecular mechanisms. Methods: The TCGA database was analyzed for the expression and clinical significance of ID proteins. The expression of ID2 was determined by qRT-PCR, immunohistochemical staining and western blot. The role of ID2 was determined by CCK-8, colony formation, wound healing, transwell and xenograft tumor assays, and the potential mechanism of ID2 in BCa was investigated by RNA sequencing. Results: ID2 expression was significantly downregulated in TCGA database and clinical samples, and high ID2 expression was associated with low-grade tumor staging and correlated with better overall survival, disease specific survival (DSS) and progress free interval (PFI). In vivo and in vitro experiments showed that knockdown of ID2 promoted proliferation, migration, invasion and metastasis of BCa cells, while overexpression of ID2 significantly inhibited cell proliferation, migration, invasion and metastasis. Mechanistically, ID2 acts as a tumor suppressor through PI3K/AKT signaling pathway to inhibit the progression and metastasis of BCa. Conclusion: Our results suggest that ID2 exerts tumor suppressive effects in BCa through PI3K/AKT signaling pathway, and altered ID2 expression can be used as a biomarker of BCa progression and metastasis.

SUBMITTER: Mao W

PROVIDER: S-EPMC8570141 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cutaneous squamous carcinoma is the second most common epithelial malignancy, associated with significant morbidity, mortality, and economic burden. However, the mechanisms underlying cSCC remain poorly understood. In this study, we identified TGM3 as a novel cSCC tumor suppressor that acts via the PI3K-AKT axis. RT-qPCR, IHC and western blotting were employed to assess TGM3 levels. TGM3-overexpression/knockdown cSCC cell lines were utilized to detect TGM3's impact on epithelial differentiation as well as tumor cell proliferation, migration, and invasion in vitro. Additionally, subcutaneous xenograft tumor models were employed to examine the effect of TGM3 knockdown on tumor growth in vivo. Finally, molecular and biochemical approaches were employed to gain insight into the tumor-suppressing mechanisms of TGM3. TGM3 expression was increased in well-differentiated cSCC tumors, whereas it was decreased in poor-differentiated cSCC tumors. Loss of TGM3 is associated with poor differentiation and a high recurrence rate in patients with cSCC. TGM3 exhibited tumor-suppressing activity by regulating cell proliferation, migration, and invasion both in vitro and in vivo. As a novel cSCC tumor differentiation marker, TGM3 expression was positively correlated with cell differentiation. In addition, our results demonstrated an interaction between TGM3 and KRT14 that aids in the degradation of KRT14. TGM3 deficiency disrupts keratinocytes differentiation, and ultimately leads to tumorigenesis. Furthermore, RNA-sequence analysis revealed that loss of TGM3 enhanced EMT via the PI3K-AKT signaling pathway. Deguelin, a PI3K-AKT inhibitor, blocked cSCC tumor growth induced by TGM3 knockdown in vivo. Taken together, TGM3 inhibits cSCC tumor growth via PI3K-AKT signaling, which could also serve as a tumor differentiation marker and a potential therapeutic target for cSCC. Proposed model depicted the mechanism by which TGM3 suppress cSCC development. TGM3 reduces the phosphorylation level of AKT and degrades KRT14. In the epithelial cell layer, TGM3 exhibits a characteristic pattern of increasing expression from bottom to top, while KRT14 and pAKT are the opposite. Loss of TGM3 leads to reduced degradation of KRT14 and activation of pAKT, disrupting keratinocyte differentiation, and eventually resulting in the occurrence of low-differentiated cSCC.

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ID2 Inhibits Bladder Cancer Progression and Metastasis via PI3K/AKT Signaling Pathway

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