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LKB1 Loss at Transcriptional Level Promotes Tumor Malignancy and Poor Patient Outcomes in Colorectal Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Liver kinase B1 (LKB1) loss by gene mutation, loss of heterozygosity, and promoter methylation rarely occurs in colorectal cancer. We wondered whether LKB1 loss could be deregulated at the transcriptional level to promote tumor progression and poor outcome in colorectal cancer.

Methods

Mechanistic studies were performed in two each of p53 wild-type (HCT116, LoVo) and p53-mutated (SW480, HT29) colon cancer cells to explore whether LKB1 loss could be deregulated by NKX2-1-mediated p53 pathway. LKB1 and NK2 homeobox 1 (NKX2-1) expressions in colorectal tumors were determined by immunohistochemistry, and the prognostic value of both molecules was assessed by Kaplan–Meier test and Cox regression model.

Results

Mechanistically, LKB1 loss at the transcriptional level due to alteration of the NKX2-1-mediated p53 pathway promotes invasiveness in colon cancer cells. The cell invasiveness induced by LKB1 loss was nearly suppressed by mammalian target of rapamycin (mTOR) inhibitor (rapamycin and everolimus) and mTOR/AKT dual inhibitor Palomid 529 (P529). Among patients, low LKB1 tumors exhibited shorter overall survival (OS) and relapse-free survival periods than high LKB1 tumors. The highest hazard ratio value for OS and relapse-free survival was observed in wild-type p53 with low LKB1/low NKX2-1 tumors and in mutated p53 with low LKB1/high NKX2-1 tumors when wild-type p53 with high LKB1/high NKX2-1 and mutated p53 with high LKB1/low NKX2-1 tumors were used as references.

Conclusions

LKB1 loss at the transcriptional level via alteration of the NKX2-1/p53 axis promotes cell invasion, consequently resulting in poor outcome in colorectal cancer patients.

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Acknowledgment

This work was supported by Grants from the National Science Council (NSC101-2632-B-040-001-MY3), Taiwan, and Taipei Medical University (TMU101-AE1-B10), Taipei, Taiwan.

Disclosures

The authors declare that they have no conflict of none.

Author information

Authors and Affiliations

  1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

    Tsung-Ying He MD, Lung-Hung Tsai PhD & Ming-Chih Chou MD, PhD

  2. Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC

    Lung-Hung Tsai PhD

  3. School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

    Chi-Chou Huang MD, PhD

  4. Department of Surgery, Chung Shan Medical University, Taichung, Taiwan, ROC

    Chi-Chou Huang MD, PhD

  5. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan, ROC

    Huei Lee PhD

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  1. Tsung-Ying He MD
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  2. Lung-Hung Tsai PhD
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  3. Chi-Chou Huang MD, PhD
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  4. Ming-Chih Chou MD, PhD
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Corresponding author

Correspondence to Huei Lee PhD.

Additional information

Tsung-Ying He and Lung-Hung Tsai have contributed equally to this work.

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He, TY., Tsai, LH., Huang, CC. et al. LKB1 Loss at Transcriptional Level Promotes Tumor Malignancy and Poor Patient Outcomes in Colorectal Cancer. Ann Surg Oncol 21 (Suppl 4), 703–710 (2014). https://doi.org/10.1245/s10434-014-3824-1

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  • DOI: https://doi.org/10.1245/s10434-014-3824-1

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