The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

Abstract

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

Mutational drivers of cancer cell migration and invasion

“…4). 198,199 Tubular and alveolar structures are transcriptionally similar and demonstrate a similar expression of epithelial and mesenchymal markers. Solid structures show an increase in mesenchymal traits but retain epithelial features.…”

“…202 Distant metastases are also frequently detected in breast cancers with single tumour cells with epithelial-like morphology, 203 and in breast cancers that express kinesin-14 (KIF14) and mitochondria-eating protein (Mieap), but lack ezrin (EZR) at the tips of torpedo-like structures. 199 The nature of torpedo-like structures, e.g., their EMT features, remains to be elucidated; however, KIF14, Mieap and EZR proteins are known to be important regulators of tumour cell migration and invasion. [204][205][206] Based on all these results, we assumed that tubular and alveolar structures show decreased invasive potential, whereas solid, trabecular and torpedo-like structures, as well as small groups of tumour cells and single tumour cells, are highly invasive.…”

Genetic co-expression networks contribute to creating predictive model and exploring novel biomarkers for the prognosis of breast cancer

“…KIF14 (Kinesin Family Member 14) is a prognostic predictor of BC 53 , 54 , 70 . It promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancers 51 , 52 .…”

Increased expression of IFN‑γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop

“…6B-E ) results demonstrated that knockdown of SOCS1 reduced SOCS1 expression in HTR8+ siSOCS1 group compared with that in the HTR + NC group, but IFN-γ intervention increased SOCS1 expression in HTR8 + IFN-γ + siSOCS1 group compared with that in the HTR + siSOCS1 group. Compared with the siNC group, western blot analysis indicated that EZR and PDGFRA expressions, which is related to cell invasion and migration respectively ( 19 , 20 ), were reduced in the siSOCS1 group; whilst the expression of cell apoptosis marker cleaved caspase3 was increased in the siSOCS1 group ( Fig. 6B and C ).…”