KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway.

Yan Liu,Su Chen,Yue-Hong Long,Shu-Qing Wang,Jing-Hua Zhang,Yu-Feng Li

doi:10.18632/oncotarget.10625

Abstract

It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams–Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.

Highlights

Mutated KRAS oncogene was identified in multiple types of cancers, such as colon cancer (35%–45%) [1, 2]
A non-transformed human intestinal primary epithelial cell (HIPEC) line was established according to the method described in Panjia’s report [6], in which the www.impactjournals.com/oncotarget wild type (WT) KRAS was detected by direct sequencing
A stable HIPEC line, which was introduced with KRASG12V mutation through transfecting pEGFP-N1human-H-RasG12V plasmid, was designated as HIPECKRASM

Summary

Introduction

Mutated KRAS oncogene was identified in multiple types of cancers, such as colon cancer (35%–45%) [1, 2]. The expression of mutant RAS glycine 12 to valine (G12V), promotes tumor initiation by activating different effectors, including Raf, phosphoinositide 3-kinase (PI3K), and Raslike (Ral) guanine nucleotide exchange factor (RalGEF) [3]. Activation of the RAS pathway can induce tumorigenic phenotypes through exploiting autocrine and paracrine signaling mechanisms in normal or tumor cell lines [4, 5]. The existing data reveal that the balance of autocrine and paracrine signaling is important to tumorigenicity induced by mutations in RAS genes. How this balance becomes disrupted is still not clear. We demonstrate that KRASG12 induces “secretion” of intracellular non-secretory protein

Methods

Results

Conclusion