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Upregulation of HGF and c-MET is Associated with Subclinical Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma

  • Endocrine Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Identification of a novel biomarker of subclinical lymph node metastasis (SLNM) in papillary thyroid microcarcinoma (PTMC) could provide important clues regarding SLNM in PTMC. We evaluated the significance of HGF and c-Met expression in surgically removed tumor tissue from PTMC patients as a predictive marker of SLNM.

Methods

We analyzed the immunohistochemical relationship between HGF and c-Met expression and SLNM in 113 surgically treated PTMC patients with clinically negative nodes presurgery. In addition, we explored whether HGF/c-Met pathway activation enhanced the in vitro migration and invasion of PTC cells.

Results

Positive immunohistochemical HGF and c-Met staining was found in 107 (95 %) and 103 (91 %) cases, respectively. The HGF staining distribution was as follows: no staining in 6 cases, weak staining in 43, moderate staining in 55, and strong staining in 9. Of the nine cases with strong HGF staining, eight (89 %) had SLNM. The c-Met staining distribution was as follows: no staining in 10 cases, weak staining in 39, moderate staining in 59, and strong staining in 5. Of the five cases with strong c-Met staining, three (60 %) had SLNM. The presence of SLNM was strongly correlated with HGF and c-Met expression in PTMC in a univariate analysis (P < 0.05). HGF overexpression was also associated with SLNM in a multivariate analysis (P < 0.05). Stimulation with exogenous HGF and constitutive activation of c-Met enhanced the migration and invasion of PTC cells in vitro by enhancing VEGF-A expression.

Conclusions

HGF/c-Met pathway activation is associated with SLNM of the central neck in PTMC.

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Acknowledgment

This work was supported by a Konkuk University Medical Center Research Grant 2011.

Disclosures

The authors indicated no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Cancer Research Institute, Chungnam National University College of Medicine, Daejeon, The Republic of Korea

    Bon Seok Koo MD, Sung Tae Seo MD, Young Hoon Yoon MD, Ki Ryun Kwon MD & Sung Ha Kim MD

  2. Research Institute for Medical Sciences and Pathology, Chungnam National University College of Medicine, Daejeon, The Republic of Korea

    Jin Man Kim MD

  3. Department of Pediatrics, Inha University College of Medicine, Incheon, The Republic of Korea

    Hye Won Kwon MD

  4. Department of Otorhinolaryngology-Head and Neck Surgery, Hallym University College of Medicine, Seoul, The Republic of Korea

    Won Jin Bae MD

  5. Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, The Republic of Korea

    Young Chang Lim MD

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  1. Bon Seok Koo MD
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  2. Jin Man Kim MD
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Correspondence to Young Chang Lim MD.

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Fig. S1

Exogenous HGF stimulates the migration and invasion of PTC cells in vitro. a Invasion assay results. Transwell chambers were used to assess cell invasiveness. TPC-1 cells were seeded on the upper membrane in the presence of recombinant human HGF (0, 10, or 30 ng/ml). After incubation for 48 h, the attached cells in the lower section of the upper chamber were counted by light microscopy. b Wound healing assay results. TPC1 cells were plated in culture plates at a density of ~1 × 105/well and grown to confluency. The monolayer was scratched with a pipette tip and washed with phosphate-buffered saline. To evaluate the effect of HGF on migratory activities, TPC-1 cells were treated with HGF (0, 10, or 30 ng/ml). Wound healing was documented by photography 24 h after scratching. c Effect of HGF on the expression of VEGF. TPC-1 cells were treated with 30 ng/ml HGF for the indicated lengths of time. Then, RNA was extracted and the expression of VEGF family members was evaluated by RT-PCR

Fig. S2

Constitutive activation of c-Met promotes invasion of PTC cells in vitro. a Western blot analysis of ligand-independent, constitutive activation of c-Met. c-Met, full-length c-Met (130 kDa); p-Met, phospho-c-Met (68 kDa). b Invasion assay results. TPC-c-Met and TPC-control cells were seeded in the upper chamber. After incubation for 48 h, invading cells attached to the lower surface of the membrane were counted. c Wound healing assay. TPC-c-Met and TPC-control cells were plated in culture plates at a density of ~1 × 105/well and grown to confluency. The monolayer was scratched with a pipette tip and washed with phosphate-buffered saline. Wound healing was documented by photography 24 h after scratching. d Effect of c-Met signaling activation on VEGF expression. TPC-c-Met and TPC-control cells were cultured in RPMI medium supplemented with 10 % FBS. Then, RNA was extracted and the expression of various VEGF family members was evaluated by semi-quantitative RT-PCR. In addition, VEGF-A protein levels was studied by Western blotting in these cells. e Effect of bevacizumab on the induction of TPC cell invasion by constitutive c-Met activation. BCM, 300 ng/ml bevacizumab, *P<0.05. f Effect of bevacizumab on the stimulation of TPC cell migration by constitutive c-Met activation. BCM, 300 ng/ml bevacizumab

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Koo, B.S., Kim, J.M., Seo, S.T. et al. Upregulation of HGF and c-MET is Associated with Subclinical Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma. Ann Surg Oncol 21, 2310–2317 (2014). https://doi.org/10.1245/s10434-014-3553-5

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  • DOI: https://doi.org/10.1245/s10434-014-3553-5

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