Sohlh2 suppresses epithelial to mesenchymal transition in breast cancer via downregulation of IL-8

Abstract

Breast cancer is one of the deadliest cancers worldwide due to its strong metastasis to other organs. Metastasis of breast cancer involves a complex set of events, including epithelial-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. We previously identified sohlh2 is a tumor suppressor in the pathogenesis of ovarian cancer. However, the functions of sohlh2 in breast cancer cell migration and invasion remain unknown. Here we report a novel sohlh2/IL-8 signaling pathway in the invasive breast cancer. We observed sohlh2 expression was downregulated in the metastatic breast cancer. Ectopic sohlh2 expression in breast cancer cells reduced EMT and inhibited cell migration and invasion in vitro, and metastasis in vivo. Moreover, the depletion of sohlh2 induced the opposite effects to ectopic sohlh2 expression. RNA-Seq data from a sohlh2 knockdown breast cancer cell line showed that after sohlh2 depletion, the mRNA level of interleukin 8 (IL-8) was significantly increased in these cancer cells, which consequently increased secretion of IL-8 protein. Using chromatin immunoprecipitation and reporter assays, we demonstrated that sohlh2 bound to IL-8 promoter and repressed its activities. The enhanced migration and invasion in sohlh2 -ablated MCF-7 cells were blocked by knockdown of IL-8 expression, while exogenous IL-8 neutralized the anti-migratory and invasive activities of sohlh2 in MDA-MB-231cells. Overall, these results demonstrate that sohlh2 functions as a tumor metastasis suppressor via suppressing IL-8 expression in breast cancer.

Sohlh2 inhibits breast cancer cell proliferation by suppressing Wnt/β‐catenin signaling pathway

“…Our previous data showed that sohlh2 could inhibit migration and invasion of breast cancer cells through the suppression of IL‐8 . In this present study, we demonstrated that transcription factor sohlh2 was involved in the regulation of breast cancer growth.…”

“…Our previous data showed that sohlh2 could inhibit migration and invasion of breast cancer cells through the suppression of IL-8. 30 In this present study, we demonstrated that transcription factor sohlh2 was involved in the regulation of breast cancer growth. Using both gain- with the observations that support the role of bhlh transcription factor as a negative regulator of cell proliferation in normal, immortalized and cancer cell lines.…”

“…Sohlh2 could repress the aggressive mesenchymal phenotype via directly downregulation of IL‐8 . It has been reported that IL‐8 drives breast cancer cell growth .…”

“…25,32 Sohlh2 could repress the aggressive mesenchymal phenotype via directly downregulation of IL-8. 30 It has been reported that IL-8 drives breast cancer cell growth. 33 Our previous data showed IL-8 knockdown only slightly blocked the inhibitory effects of sohlh2 on breast cancer cell proliferation (data not shown).…”

EMT and inflammation: inseparable actors of cancer progression

“…In mouse xenografts, ectopic expression of Shohl2 inhibits metastasis outgrowth, while Shohl2 knockdown boosts metastasis formation. Finally, Shohl2 and IL‐8 protein expressions are negatively correlated in a cohort of 12 breast cancer samples (Ji et al ., ). The CCL18/GM‐CSF/EMT loop described above links EMT to macrophages in a prometastatic pathway.…”