The transcription factor Spalt and human homologue SALL4 induce cell invasion via the dMyc-JNK pathway in Drosophila.

Jie Sun,Junzheng Zhang,Jie Shen,Dan Wang

doi:10.1242/bio.048850

Abstract

ABSTRACTCancer cell metastasis is a leading cause of mortality in cancer patients. Therefore, revealing the molecular mechanism of cancer cell invasion is of great significance for the treatment of cancer. In human patients, the hyperactivity of transcription factor Spalt-like 4 (SALL4) is sufficient to induce malignant tumorigenesis and metastasis. Here, we found that when ectopically expressing the Drosophila homologue spalt (sal) or human SALL4 in Drosophila, epithelial cells delaminated basally with penetration of the basal lamina and degradation of the extracellular matrix, which are essential properties of cell invasion. Further assay found that sal/SALL4 promoted cell invasion via dMyc-JNK signaling. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway through suppressing matrix metalloprotease 1, or basket can achieve suppression of cell invasion. Moreover, expression of dMyc, a suppressor of JNK signaling, dramatically blocked cell invasion induced by sal/SALL4 in the wing disc. These findings reveal a conserved role of sal/SALL4 in invasive cell movement and link the crucial mediator of tumor invasion, the JNK pathway, to SALL4-mediated cancer progression.This article has an associated First Person interview with the first author of the paper.

Highlights

Spalt-like (Sall) gene family proteins are zinc finger transcription factors evolutionarily conserved in many organisms from C. elegans to human beings
Jun N-terminal kinase (JNK) signaling is essential for sal/Spalt-like 4 (SALL4) activation-induced cell invasion Because the JNK pathway is an essential pathway driving tumor growth and invasion, we investigated whether the JNK pathway mediates sal/SALL4 overexpression-induced cell invasion
We deduce that concurrently expressing dMyc-RNAi and sal/SALL4 will enhance sal/SALL4-induced cell invasion and the results were as expected (Fig. 5H, I). These findings demonstrate that dMyc inhibits the JNK signaling and the Drosophila epithelial cell invasion induced by sal/SALL4 depends on dMyc-JNK signaling

Summary

Introduction

Spalt-like (Sall) gene family proteins are zinc finger transcription factors evolutionarily conserved in many organisms from C. elegans to human beings. The additional cellular and genetic data revealed that sal/SALL4-induced cell invasion depended on dMyc-JNK signaling and was independent of the apoptosis pathway. Cell migration occurred exactly in the Sal/HA positive regions (Fig. 1 C'', D'') These data demonstrate that Drosophila salm, salr and human SALL4 are highly conserved. Salr/SALL4 overexpression by dpp-Gal or in clone cells within the wing discs led to a strong increase in Mmp protein level (Fig. 3B–D). The invasive migration in sal/SALL4-overexpressing wing discs was repressed by expressing puc (Fig. 3I, J). The Mmp level, both in sal/SALL4-expressing regions and adjacent wild-type cells, was rescued (Fig. 3I, J), indicating that the non-autonomous activation of JNK pathway depends on JNK signals from the sal/SALL4-expressing cells. These findings demonstrate that dMyc inhibits the JNK signaling and the Drosophila epithelial cell invasion induced by sal/SALL4 depends on dMyc-JNK signaling

Discussion

Findings

Materials and Methods