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Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs
Author(s) -
Matsuda Yoko,
Yamashita Taro,
Ye Juanjuan,
Yasukawa Mami,
Yamakawa Keiko,
Mukai Yuri,
Machitani Mitsuhiro,
Daigo Yataro,
Miyagi Yohei,
Yokose Tomoyuki,
Oshima Takashi,
Ito Hiroyuki,
Morinaga Soichiro,
Kishida Takeshi,
Minamoto Toshinari,
Yamada Shinji,
Takei Junko,
Kaneko Mika K,
Kojima Motohiro,
Kaneko Shuichi,
Masaki Tsutomu,
Hirata Masahiro,
Haba Reiji,
Kontani Keiichi,
Kanaji Nobuhiro,
Miyatake Nobuyuki,
Okano Keiichi,
Kato Yukinari,
Masutomi Kenkichi
Publication year - 2022
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5876
Subject(s) - telomerase reverse transcriptase , cancer research , lung cancer , cancer , biology , immunohistochemistry , pancreatic cancer , telomerase , medicine , pathology , immunology , biochemistry , gene
Recent evidence indicates that RNA‐dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere‐independent manner. Non‐canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p‐hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p‐hTERT antibody. To clarify the clinical relevance of p‐hTERT, we developed a specific monoclonal antibody and determined the diagnostic and prognostic value of p‐hTERT in cancer specimens using a large cohort. A monoclonal antibody for phosphorylated hTERT (p‐hTERT) at threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of formalin‐fixed, paraffin‐embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and kidney cancers. We detected elevated p‐hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p‐hTERT expression was an independent prognostic factor for lung, pancreatic, and liver cancers. Furthermore, p‐hTERT expression was associated with immature and aggressive features, such as adenosquamous carcinoma (lung and pancreas), invasive type of cancer (lung), high serum alpha‐fetoprotein level (liver), and triple‐negative status (breast). In conclusion, RdRP activity indicated by p‐hTERT expression predicts aggressive cancer phenotypes in various types of cancer. Thus, p‐hTERT is a novel biomarker for the diagnosis of aggressive cancers with a poor prognosis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.