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Akt-mediated Ephexin1-Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation.

ABSTRACT:

Abstrct

Ephexin1 was reported to be highly upregulated by oncogenic Ras, but the functional consequences of this remain poorly understood. Here, we show that Ephexin1 is highly expressed in colorectal cancer (CRC) and lung cancer (LC) patient tissues. Knockdown of Ephexin1 markedly inhibited the cell growth of CRC and LC cells with oncogenic Ras mutations. Ephexin1 contributes to the positive regulation of Ras-mediated downstream target genes and promotes Ras-induced skin tumorigenesis. Mechanically, Akt phosphorylates Ephexin1 at Ser16 and Ser18 (pSer16/18) and pSer16/18 Ephexin1 then interacts with oncogenic K-Ras to promote downstream MAPK signaling, facilitating tumorigenesis. Furthermore, pSer16/18 Ephexin1 is associated with both an increased tumor grade and metastatic cases of CRC and LC, and those that highly express pSer16/18 exhibit poor overall survival rates. These data indicate that Ephexin1 plays a critical role in the Ras-mediated CRC and LC and pSer16/18 Ephexin1 might be an effective therapeutic target for CRC and LC.

SUBMITTER: Kim J

PROVIDER: S-EPMC8553951 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Akt-mediated Ephexin1-Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation.

Kim Jeeho J Jeon Young Jin YJ Lim Sung-Chul SC Ryu Joohyun J Lee Jung-Hee JH Chang In-Youb IY You Ho Jin HJ

Cell death & disease 20211028 11

<h4>Abstrct</h4>Ephexin1 was reported to be highly upregulated by oncogenic Ras, but the functional consequences of this remain poorly understood. Here, we show that Ephexin1 is highly expressed in colorectal cancer (CRC) and lung cancer (LC) patient tissues. Knockdown of Ephexin1 markedly inhibited the cell growth of CRC and LC cells with oncogenic Ras mutations. Ephexin1 contributes to the positive regulation of Ras-mediated downstream target genes and promotes Ras-induced skin tumorigenesis. ...[more]

PMID: 34711817

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Project description:Background: KIFC3, belongs to kinesin superfamily proteins (KIFs), is well known for its role in intracellular cargo movement. KIFC3 has been identified as a docetaxel resistance gene in breast cancer cells, however, the role of KIFC3 and its potential mechanism in colorectal cancer (CRC) remains elusive. Objectives: We aims to investigate the effects of KIFC3 in proliferation, migration, and invasion in CRC as well as the potential mechanism inside. Methods: We investigated the expression of KIFC3 in the Oncomine, Gene Expression Profiling Interactive Analysis databases. The KIFC3 protein expression and mRNA level in CRC cells were evaluated by western blot and qRT-PCR. Cell proliferation ability was detected by CCK-8, EdU, colony formation assay and xenograft tumor in nude mice. Flow cytometry was used to detect the cell cycle. The effect of KIFC3 on the epithelial-to-mesenchymal transition (EMT) was investigated by transwell and wound healing assay. The association of KIFC3 with EMT and PI3K/AKT/mTOR signaling pathway were measured by western blot and immunofluorescence staining. Results: The expression of KIFC3 was higher in CRC tissues than normal colorectal tissue, and was negatively correlated with the overall survival of patients with CRC. KIFC3 silencing inhibited the proliferation, migration and invasion of CRC cells. Meanwhile, it could decrease the number of cells in S phase. KIFC3 silencing inhibited the expression of proliferating cell nuclear antigen, Cyclin A2, Cyclin E1, and CDK2 and increased the expression of p21 and p53. KIFC3 overexpression promoted the G1/S phase transition. KIFC3 silencing inhibited the EMT process, which decreased the level of N-cadherin, Vimentin, SNAIL 1, TWIST, MMP-2, MMP-9 and increased E-cadherin, while KIFC3 overexpression show the opposite results. Furthermore, the knockdown of KIFC3 suppressed the EMT process by modulating the PI3K/AKT/mTOR signaling pathway. KIFC3 silencing decreased the expression of phosphorylated PI3K, AKT, mTOR, but total PI3K, AKT, mTOR have no change. Inversely, the upregulation of KIFC3 increased the expression of phosphorylated PI3K, AKT and mTOR, total PI3K, AKT, mTOR have no change. In a xenograft mouse model, the depletion of KIFC3 suppressed tumor growth. the increased expression levels of KIFC3 could enhance the proliferation, migration and invasion of CRC cells, and enhance the EMT process through the PI3K/AKT/mTOR pathway. Conclusion: Our study substantiates that KIFC3 can participate in the regulation of CRC progression by which regulates EMT via the PI3K/AKT/mTOR axis.

Dataset Information

Akt-mediated Ephexin1-Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation.

Abstrct

Publications

Akt-mediated Ephexin1-Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation.

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