HOXA13 promotes gastric cancer progression partially via the FN1-mediated FAK/Src axis

Zhiwei Qin,Chongzhi Zhou

doi:10.1186/s40164-022-00260-7

Zhiwei Qin, Chongzhi Zhou

Open Access

https://doi.org/10.1186/s40164-022-00260-7

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Abstract

BackgroundGastric cancer (GC) is one of the most common cancers causing a poor prognosis worldwide. HOXA13, as a member of the homeobox (HOX) family, is involved in the regulation of cancer progression and has attracted increasing attention, as a potential novel target for anticancer strategies. However, the significance of HOXA13 in GC remains unclear. This article aims to explore the potential mechanism of HOXA13 in GC progression.MethodsQuantitative real-time PCR was carried out to detect the expression of HOXA13 and FN1 and the correlation between HOXA13 and FN1 in GC tissues. In vitro assays were conducted to investigate the role of HOXA13 and FN1 in the malignant phenotypes of GC cells and the function of HOXA13 in the activation of the FAK/Src axis in GC cells. Coimmunoprecipitation was performed to reveal the relationship between ITGA5, ITGB1 and FN1 in GC cells. A dual luciferase assay was performed to assess miR-449a-targeted regulation of HOXA13 expression.ResultsQuantitative real-time PCR verified that HOXA13 was elevated and positively correlated with FN1 in GC. In vitro and in vivo assays demonstrated that high expression of HOXA13 promoted GC progression, especially metastasis. Mechanistically, rescue experiments, chromatin immunoprecipitation and dual luciferase assays revealed that HOXA13 directly bound to the FN1 promoter region to enhance the activation of the FAK/Src axis, leading to GC cell proliferation and metastasis. Furthermore, the result of a dual luciferase assay suggested that HOXA13 was directly targeted by miR-449a.ConclusionsOur results show that HOXA13 is a positive regulator of the FAK/Src axis mediated by FN1 in GC and promotes GC progression. Thus, targeting HOXA13, together with FN1, may provide a novel prospective anticancer strategy.

Highlights

Gastric cancer (GC) is one of the most common cancers causing a poor prognosis worldwide
Homeobox A13 (HOXA13) expression was elevated in GC The Quantitative real-time polymerase chain reaction (qRT-PCR) results showed that HOXA13 was elevated in 83.61% (51/61) of GC tissues compared with adjacent normal tissues (Fig. 1a)
We found that siFN1 could suppress the Focal adhesion kinase (FAK)/ Src axis activation induced by HOXA13 overexpression, Fig. 6 Fibronectin 1 (FN1) promoted malignant phenotypes in GC cells. a Cell Counting Kit-8 (CCK-8) assay was used for GC cell proliferation. b Flow cytometry analysis was used to evaluate GC cell apoptosis. c Angiogenesis ability of GC cells was detected by tube formation assay

Summary

Introduction

Gastric cancer (GC) is one of the most common cancers causing a poor prognosis worldwide. HOXA13, as a member of the homeobox (HOX) family, is involved in the regulation of cancer progression and has attracted increasing attention, as a potential novel target for anticancer strategies. As a member of the HOX gene family, HOXA13 has been implicated as the critical factor of the progression of FAK/Src, a formed dual-kinase complex, is involved in the regulation of the PI3K-Akt signaling pathway and Erk signaling pathway, an important component of the. Fibronectin 1 (FN1) plays an important role in the activation of the FAK/Src axis. FN1 binds to transmembrane glycoprotein signaling receptors, especially integrin α5 (ITGA5) and integrin β1 (ITGB1) [10,11,12,13], and increases the kinase activities of downstream targets, including the FAK/Src, Akt and Erk1/2 signaling cascades [8, 14]. According to the above findings, we believe that it is worth further studying whether FN1 and the FAK/Src axis participate in the promotion of GC by HOXA13

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