Journal
ONCOTARGET
Volume 6, Issue 39, Pages 41916-41928Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6019
Keywords
metastasis; GalNAc-T14; WNT/TCF pathway; HOXB9; invasion
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Funding
- National Research Foundation of Korea (NRF) [2014R1A2A2A01005970, 2011-0030043, HI14C3365]
- Korea Healthcare technology R&D Project, Ministry for Health & Welfare Affairs
- National Research Foundation of Korea [2014R1A2A2A01005970] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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While metastasis, the main cause of lung cancer-related death, has been extensively studied, the underlying molecular mechanism remains unclear. A previous clinicogenomic study revealed that expression of N-acetylgalactosaminyltransferase (GalNAc-T14), is highly inversely correlated with recurrence-free survival in those with non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism(s) has not been determined. Here, we showed that GalNAc-T14 expression was positively associated with the invasive phenotype. Microarray and biochemical analyses revealed that HOXB9, the expression of which was increased in a GalNAc-T14-dependent manner, played an important role in metastasis. GalNAc-T14 increased the sensitivity of the WNT response and increased the stability of the beta-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of beta-catenin in GalNAc-T14-expressing cancer cells suppressed HOXB9 expression and invasion. A meta-analysis of clinical genomics data revealed that expression of GalNAc-T14 or HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting beta-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC.
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