Abstract
BackgroundHhex(human hematopoietically expressed homeobox), also known as PRH, is originally considered as a transcription factor to regulate gene expression due to its homebox domain. Increasing studies show that Hhex plays a significant role in development, including anterior–posterior axis formation, vascular development and HSCs self-renewal etc. Hhex is linked to many diseases such as cancers, leukemia, and type-2 diabetes. Although Hhex is reported to inhibit cell migration and invasion of breast and prostate epithelial cells by upregulating Endoglin expression, the effect and molecular mechanism for lung cancer cell motility regulation remains elusive.MethodsHuman non-small cell lung cancer cells and HEK293FT cells were used to investigate the molecular mechanism of Hhex regulating lung cancer cell migration by using Western blot, immunoprecipitation, wound-healing scratch assay, laser confocal.ResultsOur data indicated that Hhex could inhibit cell migration and cell protrusion formation in lung cancer cells. In addition, Hhex inhibited CFL1 phosphorylation to keep its F-actin-severing activity. RHOGDIA was involved in Hhex-induced CFL1 phosphorylation regulation. Hhex enhanced RHOGDIA interaction with RHOA/CDC42, thus maintaining RHOA/CDC42 at an inactive form.ConclusionCollectively, these data indicate that Hhex inhibited the activation of RHOA/CDC42 by enhancing interaction of RHOGDIA with RHOA/CDC42, and then RHOA/ CDC42-p-CFL1 signaling pathway was blocked. Consequently, the formation of Filopodium and Lamellipodium on the cell surface was suppressed, and thus the ability of lung cancer cells to migrate was decreased accordingly. Our findings show Hhex plays an important role in regulating migration of lung cancer cells and may provide a potential target for lung cancer therapy.FSYn6j34J4ZMCghGVb9zTbVideo abstract
Highlights
Haematopoietically expressed homeobox (Hhex)(human hematopoietically expressed homeobox), known as PRH, is originally considered as a transcription factor to regulate gene expression due to its homebox domain
We found that level of Hhex reduced in multiple cancer tissues was reduced including Bladder Urothelial Carcinoma (BLCA), Breast invasive carcinoma (BRCA), Colon adenocarcinoma (COAD), Kidney Chromophobe (KICH), Kidney renal papillary cell carcinoma (KIRP), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Rectum adenocarcinoma (READ), Thyroid carcinoma (THCA) and Uterine Corpus Endometrial Carcinoma (UCEC), compared with normal tissues in the GEPIA database (Additional file 1: Figure S1)
(See figure on page.) Fig. 1 Hhex was downregulated and inhibited cell migration in lung cancer cells. a Box plots of Hhex mRNA levels determined from four Oncomine datasets, namely Hou Lung, Landi Lung, Okayama Lung and Selamat Lung, (***P < 0.001; P values were obtained using two-tailed Student’s t-tests). b KM plotter analysis of the relation between Hhex gene expression and (OS) in lung cancer patients. c Control siRNA (CTRL) or HHEX siRNA (#1) and (#2) was transfected into H1792 cells
Summary
Hhex(human hematopoietically expressed homeobox), known as PRH, is originally considered as a transcription factor to regulate gene expression due to its homebox domain. Hhex is linked to many diseases such as cancers, leukemia, and type-2 diabetes. Hhex is reported to inhibit cell migration and invasion of breast and prostate epithelial cells by upregulating Endoglin expression, the effect and molecular mechanism for lung cancer cell motility regulation remains elusive. The incidence and mortality of lung cancer increases fast [2]. The problem with cancer treatment lied in its metastasis, which accounts for 90% of cancer-related deaths [3, 4]. Tumor metastasis from primary sites to secondary sites is a complex process. Capacity enhancement of cell motility is an obvious characteristic of tumor cells [5, 6]. Regulated by ARHGDI, RHOGAP and RHOGEF, those small-GTPases are transformed between two different forms: GTP-binding (active) or GDP-binding
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