Akt-mediated Ephexin1\u2013Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation

Jeeho Kim,Young Jin Jeon,Jung-Hee Lee,Sung-Chul Lim,Ho Jin You,Joohyun Ryu,In-Youb Chang

doi:10.1038/s41419-021-04332-0

Jeeho Kim, Young Jin Jeon + Show 5 more

Open Access

https://doi.org/10.1038/s41419-021-04332-0

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Abstract

AbstrctEphexin1 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.

Highlights

Oncogenic Ras mutations are frequently observed in solid tumor cells and are present in pancreatic cancer, colorectal cancer (CRC), and lung cancer (LC) [1, 2]
Ephexin1 enhances proliferation in CRC and LC cells To determine whether Ephexin1 expression is associated with tumorigenesis, we first analyzed Ephexin1 expression using RNA sequencing (RNA-seq) data from clinical samples included in
We found that the proliferative ability (Fig. 1E) and anchorage-independent growth (Fig. 1F) of the Ephexin1 knockdown cells were significantly inhibited compared to their control cells

Summary

Introduction

Oncogenic Ras mutations are frequently observed in solid tumor cells and are present in pancreatic cancer, colorectal cancer (CRC), and lung cancer (LC) [1, 2]. Mutational activation of K-Ras in these tissues is sufficient to initiate neoplasia in mice [3,4,5]. Understanding the mechanisms behind Ras-induced oncogenesis is an important goal in cancer therapy. A significant consequence of Ras-mediated signal transduction is the altered expression of a large number of genes. Many aspects of the molecular mechanism underlying Ras-induced tumorigenesis and possible therapeutic targeting remain difficult to identify

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