Oncotarget

Research Papers:

GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma

Ok-Seon Kwon, Ensel Oh, Jeong-Rak Park, Ji-Seon Lee, Gab-Yong Bae, Jae-Hyung Koo, Hyungbum Kim, Yoon-La Choi, Young Soo Choi, Jhingook Kim and Hyuk-Jin Cha _

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Oncotarget. 2015; 6:41916-41928. https://doi.org/10.18632/oncotarget.6019

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Abstract

Ok-Seon Kwon1, Ensel Oh2, Jeong-Rak Park1, Ji-Seon Lee1, Gab-Yong Bae1, Jae-Hyung Koo3, Hyongbum Kim4, Yoon-La Choi5, Young Soo Choi6, Jhingook Kim6, Hyuk-Jin Cha1

1College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea

2Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea

3Department of Brain and Cognitive Sciences, DGIST Daegyu, Republic of Korea

4Department of Pharmacology, Yonsei University College of Medicine, Seoul

5Department of Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea

6Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea

Correspondence to:

Hyuk-Jin Cha, e-mail: [email protected]

Jhingook Kim, e-mail: [email protected]

Keywords: metastasis, GalNAc-T14, WNT/TCF pathway, HOXB9, invasion

Received: July 30, 2015     Accepted: October 15, 2015     Published: October 26, 2015

ABSTRACT

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 β-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of β-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 β-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC.


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