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Versican Secreted by Cancer-Associated Fibroblasts is a Poor Prognostic Factor in Hepatocellular Carcinoma

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

Abstract

Background

Hepatocellular carcinoma (HCC) is highly recurrent. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, promote malignancy; however, the mechanisms underlying their actions are obscure. We aimed to identify CAF-specific proteins in HCC and determine whether they could be potential therapeutic targets.

Methods

Using comprehensive proteomic analysis of CAFs and noncancerous fibroblasts (NFs) primary-cultured from resected HCC specimens from the same patients, CAF-specific proteins were identified. Immunohistochemistry for versican (VCAN) was performed on cancerous tissues obtained from 239 patients with HCC. Conditioned medium from CAFs transfected with siRNA for VCAN was analyzed in vitro.

Results

CAFs significantly promoted HCC cell proliferation, migration, and invasion (p < 0.01, 0.01, and 0.01, respectively) compared with NFs. VCAN was upregulated in CAFs, and its stromal level correlated with poor differentiation (p = 0.009) and positive vascular invasion (p = 0.003). Stromal VCAN level was also associated with significantly lower overall (p = 0.002) and relapse-free (p < 0.001) survival rates. It also independently predicted prognosis and recurrence. VCAN-knockdown CAFs significantly suppressed HCC cell migration and invasion compared with negative control.

Conclusions

VCAN secreted from CAFs promoted malignant transformation of HCC cells and has potential as a new therapeutic target in HCC.

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Acknowledgment

The authors thank all the patients who provided specimens for this study and the Department of Gastroenterological Surgery I at Hokkaido University Hospital for sample collection. They also thank Naoki Okada for preparing the tissue microarrays and Nozomi Kobayashi, Ayae Nange, and Asami Okumura for their technical assistance on the experiments. Thanks to Editage (www.editage.jp) for the English language review.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Koichi Kato MD, Moto Fukai MD, PhD, Takahiro Hayasaka PhD, Toshiya Kamiyama MD, PhD & Akinobu Taketomi MD, PhD

  2. Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo, Japan

    Kanako C. Hatanaka MD, PhD & Yutaka Hatanaka PhD

  3. Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan

    Kanako C. Hatanaka MD, PhD

  4. Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Akira Takasawa MD, PhD & Tomoyuki Aoyama PhD

  5. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan

    Yoshihiro Matsuno MD, PhD

  6. Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan

    Yutaka Hatanaka PhD

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  1. Koichi Kato MD
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  2. Moto Fukai MD, PhD
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  4. Akira Takasawa MD, PhD
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  7. Yoshihiro Matsuno MD, PhD
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Corresponding author

Correspondence to Akinobu Taketomi MD, PhD.

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Disclosures

This study was supported by the Japan Agency for Medical Research and Development (AMED) under the Grant number JP20fk0210041. The authors declare no conflict of interest

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Kato, K., Fukai, M., Hatanaka, K.C. et al. Versican Secreted by Cancer-Associated Fibroblasts is a Poor Prognostic Factor in Hepatocellular Carcinoma. Ann Surg Oncol 29, 7135–7146 (2022). https://doi.org/10.1245/s10434-022-11862-0

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  • DOI: https://doi.org/10.1245/s10434-022-11862-0

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