HOXC6 Regulates the Epithelial-Mesenchymal Transition through the TGF-β/Smad Signaling Pathway and Predicts a Poor Prognosis in Glioblastoma

Abstract

Background. The HOX gene family of transcription factors, characterized by conserved homeodomains, is positively correlated with the resistance to chemotherapy drugs and poor prognosis, as well as the initiating potential of gliomas. However, there are few studies regarding the HOXC6 gene in glioma cells. Therefore, in the present study, we explored the regulatory roles and detailed mechanisms underlying the relationship between HOXC6 and the progression of GBM. Methods. The expression levels and prognostic value of HOXC6 in GBM were evaluated using the data obtained from the GCCA, GEPIA, and ONCOMINE databases. The relationship between GBM prognosis and levels of HOXC6 was identified using Kaplan-Meier curves. The protein levels of HOXC6 in GBM and adjacent normal tissues were identified via Western blot and immunohistochemistry (IHC) staining methods. Lentiviruses containing full-length HOXC6 and HOXC6 specific siRNA sequences were used to overexpress and knock down, respectively, the expression of HOXC6 in U87 and U251 cells. The role of HOXC6 in the regulation of migration and proliferation of GBM cells was accessed using Transwell, wound healing, CCK-8, and colony formation assays. The activation of the TGF-β/Smad signaling pathway was detected via Western blotting. Results. Compared to normal tissues and control cells, GBM tissues and cell lines showed higher expressions of HOXC6. The expression of HOXC6 was associated with disease-free and the overall survival of GBM patients. Additionally, positive correlations between the expression of HOXC6 and the migration and proliferation of GBM cells were observed in vitro. The mechanistic analyses indicated that HOXC6 exerts its promotive effect on the progression and invasion of glioma cells by promoting the activation of the EMT and TGF-β/Smad signaling pathways. Conclusions. HOXC6 enhances the migration and proliferation of GBM by activating the EMT signaling pathway.

Predicting the prognosis of glioma patients with TERT promoter mutations and guiding the specific immune profile of immune checkpoint blockade therapy

“…HOXC6 was found to be overexpressed in clinical glioma samples, and its knockdown stimulated the WIF-1/Wnt signaling pathway and induced cell cycle arrest and apoptosis in U87 glioma cells [ 17 ]. HOXC6 was also found to regulate EMT signaling, and was proposed as a new immunotherapeutic target for gliomas [ 18 , 19 ]. The orthopedia homeobox (OTP) gene, a member of the homeodomain (HD) family, plays an essential role in development and cell-fate specification of the hypothalamic neuroendocrine system in vertebrates [ 20 ].…”

HOXC6‐mediated transcriptional activation of ENO2 promotes oral squamous cell carcinoma progression through the Warburg effect

“…HOXC6, integral to the homeobox gene family, plays a pivotal role in encoding transcription factors essential for orchestrating the morphogenesis of multicellular organisms. [46,47] It has been implicated in various cancers, promoting proliferation, migration, and poor prognosis in glioma, [48] keloid fibroblasts, [49] glioblastoma, [50] colorectal cancer, [23] and pancreatic ductal adenocarcinoma. [24] While abnormal expressions of HOXC6 have been previously identified in OSCC tissues, [51] its correlation with the Warburg Effect had not been explored.…”