Id4 Suppresses the Growth and Invasion of Colorectal Cancer HCT116 Cells through CK18-Related Inhibition of AKT and EMT Signaling

Abstract

Id4 is one of the inhibitors of DNA-binding proteins (Id) and involved in the pathogenesis of numerous cancers. The specific mechanism underlying the Id4-mediated regulation of proliferation, invasion, and metastasis of colorectal cancer (CRC) cells is still largely unclear. In the present study, results showed CRC cells had a lower baseline Id4 expression than normal intestinal epithelial NCM460 cells. In order to explore the role of Id4 in the tumorigenicity, CRC HCT116 cells with stable Id4 expression were used, and results showed Id4 overexpression arrested the cell cycle at the G0/G1 phase, inhibited the cell proliferation and the colony formation, as well as suppressed the migration and invasion. In the in vivo model, Id4 overexpression inhibited the tumor growth and metastasis in the nude mice. Furthermore, Id4 overexpression upregulated the expression of proteins associated with cell proliferation, inhibited the PI3K/AKT pathway, and suppressed epithelial-mesenchymal transition (EMT) of HCT116 cells. Moreover, Id4 significantly decreased cytokeratin 18 (CK18) expression, but CK18 overexpression in Id4 expressing HCT116-Id4 cells rescued the activation of AKT, p-AKT, MMP2, MMP7, and E-cadherin. Collectively, our study indicated Id4 may inhibit CRC growth and metastasis through inhibiting the PI3K/AKT pathway in a CK18-dependent manner and suppressing EMT. Id4 may become a target for the treatment of CRC.

Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer

“…Previous research has reported that ID4 acts as a tumor suppressor in CRC progression [ 21 , 22 ]. We conducted the rescue experiments to confirm the interaction between circTMEM59 and ID4 of CRC.…”

“…ID4 was identified as a target of miR-668-3p through luciferase reporter and RIP assays, which was abnormal in different types of cancer [ 37 – 39 ]. Importantly, ID4 is reportedly an inhibitor of CRC progression [ 21 , 22 ]. As expected, ID4 was simultaneously decreased in CRC tissues and larger tissues compared with that in adjacent tissues and smaller tissues.…”

The Expression Profile, Clinical Application and Potential Tumor Suppressing Mechanism of hsa_circ_0001675 in Head and Neck Carcinoma

“…In addition, due to differences in regulatory mechanisms, a gene can have different functions in the same organ carcinomas. In colorectal cancer, inhibitors of DNA-binding protein 4 (ID4) can promote tumorigenesis by targeting brain-derived neurotrophic factor (BDNF) (37), and can also inhibit tumor growth and metastasis by inhibiting PI3K/AKT pathway and inhibiting epithelial-mesenchymal transition (EMT) in a CK18-Related manner (38). Therefore, the hsa_circ_0001675/miR577/TESC pathway in HNC needs to be experimentally verified, and the specific mechanism of TESC needs further study.…”

PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells

“…Id4 inactivated AKT and PI3K, suppressing CRC cell proliferation through modulating PI3K/AKT signaling. Id4 mitigated the EMT process as it up regulated TIMP1/2 and down regulated the snail, slug, twist, β-catenin, MMP2, and MMP7 [ 51 ]. GATA1 is a critical modulator of erythroid cell apoptosis, proliferation, and differentiation.…”