HOXC9 promotes gastric cancer cell proliferation, invasion, and migration via regulating HIF-1 pathway.

Background

Gastric cancer (GC) remains a major malignancy associated with rapid progression and poor clinical outcomes. Elucidating the molecular events responsible for GC advancement, and the identification of key regulatory targets, is of critical importance for improving patient prognosis.

Methods

Integrated bioinformatics analyses of public datasets identified HOXC9 as a candidate gene. Its expression was validated using independent database analyses, and mRNA/protein expression assessment. Functional assays following HOXC9 overexpression or knockdown were performed to evaluate malignant phenotypes and metabolic changes in GC cells. We employed RNA-seq to profile transcriptomic alterations upon HOXC9 modulation, and their functional relevance was further validated.

Results

Database analyses identified HOXC9 as an unfavorable prognostic factor in GC, and its increased expression was subsequently verified in HGC-27 and MKN-45. Functional assays demonstrated that overexpression of HOXC9 markedly enhanced the proliferative, invasive, and migratory capacities, whereas silencing of HOXC9 produced the opposite effects. Transcriptomic profiling suggested that HOXC9 regulates the HIF-1 pathway, and an inverse association between HOXC9 and HIF1A was observed. Mechanistically, overexpression of HOXC9 accelerated malignant characteristics via modulation of the HIF-1 pathway, accompanied by increased ATP and lactate production and reduced glucose levels. In contrast, knockdown of HOXC9 exerted opposing effects.

Conclusions

HOXC9 drives GC progression through activating the HIF-1 pathway, highlighting a novel regulatory axis with potential implications for GC intervention.