p62/sequestosome 1 in human colorectal carcinoma as a potent prognostic predictor associated with cell proliferation

  • Shun Nakayama
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Hideaki Karasawa
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Takashi Suzuki
    Department of Pathology and Histotechnology Tohoku University Graduate School of Medicine Sendai Japan
  • Shinichi Yabuuchi
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Kiyoshi Takagi
    Department of Pathology and Histotechnology Tohoku University Graduate School of Medicine Sendai Japan
  • Takashi Aizawa
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Yoshiaki Onodera
    Department of Anatomic Pathology Tohoku University Graduate School of Medicine Sendai Japan
  • Yasuhiro Nakamura
    Department of Anatomic Pathology Tohoku University Graduate School of Medicine Sendai Japan
  • Mika Watanabe
    Department of Pathology Tohoku University Hospital Sendai Japan
  • Fumiyoshi Fujishima
    Department of Pathology Tohoku University Hospital Sendai Japan
  • Hiroshi Yoshida
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Takanori Morikawa
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Tomohiko Sase
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Takeshi Naitoh
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Michiaki Unno
    Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
  • Hironobu Sasano
    Department of Pathology Tohoku University Hospital Sendai Japan

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<jats:title>Abstract</jats:title><jats:p>p62/sequestosome 1 (p62) is a multi‐domain protein that functions as a receptor for ubiquitinated targets in the selective autophagy and serves as a scaffold in various signaling cascades. p62 have been reported to be up‐regulated in several human malignancies, but the biological roles and significance of p62 are still poorly understood in colorectal carcinoma. We immunohistochemically evaluated p62 in 118 colorectal adenocarcinoma and 28 colorectal adenoma cases. We used four colon carcinoma cells (<jats:styled-content style="fixed-case">HCT</jats:styled-content>8, <jats:styled-content style="fixed-case">HT</jats:styled-content>29, <jats:styled-content style="fixed-case">COLO</jats:styled-content>320, and <jats:styled-content style="fixed-case">SW</jats:styled-content>480) in the in vitro studies. p62 immunoreactivity was detected in 11% of colorectal adenoma cases and 31% of adenocarcinoma cases, while it was negligible in the normal epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis, and it turned out to be an independent adverse prognostic factor in colorectal cancer patients. Following in vitro studies revealed that <jats:styled-content style="fixed-case">HCT</jats:styled-content>8 and <jats:styled-content style="fixed-case">HT</jats:styled-content>29 cells transfected with p62‐specific si<jats:styled-content style="fixed-case">RNA</jats:styled-content> showed significantly decreased cell proliferation activity, whereas <jats:styled-content style="fixed-case">COLO</jats:styled-content>320 and <jats:styled-content style="fixed-case">SW</jats:styled-content>480 cells transfected with p62 expression plasmid showed significantly increased cell proliferation activity. The p62‐mediated cell proliferation was not associated with the autophagy activity. These findings suggest that p62 promotes the cell proliferation mainly as a scaffold protein, and that the p62 status is a potent prognostic factor in colorectal carcinoma patients.</jats:p>

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