PMID- 31019292 OWN - NLM STAT- MEDLINE DCOM- 20200629 LR - 20230216 IS - 1530-0307 (Electronic) IS - 0023-6837 (Linking) VI - 99 IP - 9 DP - 2019 Sep TI - CD271 is a negative prognostic factor and essential for cell proliferation in lung squamous cell carcinoma. PG - 1349-1362 LID - 10.1038/s41374-019-0246-5 [doi] AB - Squamous cell carcinoma is a major type of cancer in the lung. While several therapeutic target molecules for lung adenocarcinoma have been identified, little is known about lung squamous cell carcinoma (LSCC). We recently reported that CD271 (p75 neurotrophin receptor) serves as a marker for tumor initiation and is a key regulator of cell proliferation in hypopharyngeal squamous cell carcinoma. In this study, we found that CD271 was also expressed in squamous cell carcinoma, but not in adenocarcinoma, of several tissues, including the lung, and the expression of CD271 was associated with a poor prognosis in LSCC. To examine CD271's role in LSCC, we established xenograft cell lines from LSCC patients. Within the sorted live LSCC cell population, the CD271(high) cells were primarily cycling through the G(2)/M phase, while the CD271(low) cells were mostly in the G(0) phase. CD271 knockdown in the LSCC cells completely suppressed their proliferation and tumor-formation capability, and increased their cell-cycle arrest in the G(0) phase. In the CD271-knockdown cells, ERK-phosphorylation was decreased, while no change was observed in the IkappaBalpha-phosphorylation, p65-phosphorylation, or Akt-phosphorylation. Treatment with the MEK inhibitor U0126 decreased the LSCC cells' proliferation capability. Microarray analysis revealed that CD271 knockdown attenuated the RAS-related pathways. The knockdown of TrkB, which forms a heterodimer with CD271 and accelerates its downstream signaling, partially inhibited the LSCC cell proliferation. These results indicated that LSCC exclusively depends on CD271 for cell proliferation, in part through ERK-signaling activation, and CD271 is a promising target for LSCC therapy. FAU - Mochizuki, Mai AU - Mochizuki M AD - Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Nakamura, Mao AU - Nakamura M AD - Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Sibuya, Rie AU - Sibuya R AD - Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Okazaki, Toshimasa AU - Okazaki T AD - Department of Thoracic Surgery, Miyagi Cancer Center, Natori, Japan. FAU - Abe, Jiro AU - Abe J AD - Department of Thoracic Surgery, Miyagi Cancer Center, Natori, Japan. FAU - Nakagawa, Takayuki AU - Nakagawa T AD - Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Takahashi, Satomi AU - Takahashi S AD - Department of Thoracic Surgery, Miyagi Cancer Center, Natori, Japan. FAU - Yamazaki, Tomoko AU - Yamazaki T AD - Department of Head and Neck Medical Oncology, Miyagi Cancer Center, Natori, Japan. FAU - Imai, Takayuki AU - Imai T AD - Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Japan. FAU - Takano, Atsushi AU - Takano A AD - Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. AD - Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan. FAU - Ito, Hiroyuki AU - Ito H AD - Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan. FAU - Yokose, Tomoyuki AU - Yokose T AUID- ORCID: 0000-0002-9403-9592 AD - Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan. FAU - Miyagi, Yohei AU - Miyagi Y AD - Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan. FAU - Daigo, Yataro AU - Daigo Y AD - Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. AD - Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan. FAU - Sato, Ikuro AU - Sato I AD - Department of Pathology, Miyagi Cancer Center, Natori, Japan. FAU - Satoh, Kennichi AU - Satoh K AD - Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan. AD - Division of Gastroenterology and Hepatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan. FAU - Sugamura, Kazuo AU - Sugamura K AD - Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Yamaguchi, Kazunori AU - Yamaguchi K AD - Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan. FAU - Tamai, Keiichi AU - Tamai K AD - Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan. tamaikeiichi@med.tohoku.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190424 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - 0 (Biomarkers, Tumor) RN - 0 (NGFR protein, human) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, Nerve Growth Factor) SB - IM MH - Aged MH - Aged, 80 and over MH - Animals MH - Biomarkers, Tumor MH - Carcinoma, Squamous Cell/diagnosis/*metabolism/mortality MH - Cell Line, Tumor MH - Cell Movement/genetics MH - Cell Proliferation/*genetics MH - Disease-Free Survival MH - Female MH - Humans MH - Lung Neoplasms/diagnosis/*metabolism/mortality MH - Male MH - Mice, Inbred NOD MH - Mice, SCID MH - Middle Aged MH - *Nerve Tissue Proteins/genetics/metabolism MH - Prognosis MH - *Receptors, Nerve Growth Factor/genetics/metabolism EDAT- 2019/04/26 06:00 MHDA- 2020/07/01 06:00 CRDT- 2019/04/26 06:00 PHST- 2018/08/26 00:00 [received] PHST- 2019/02/28 00:00 [accepted] PHST- 2019/02/26 00:00 [revised] PHST- 2019/04/26 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2019/04/26 06:00 [entrez] AID - S0023-6837(22)02594-6 [pii] AID - 10.1038/s41374-019-0246-5 [doi] PST - ppublish SO - Lab Invest. 2019 Sep;99(9):1349-1362. doi: 10.1038/s41374-019-0246-5. Epub 2019 Apr 24.