DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells

Naoki Katase, Shin Ichiro Nishimatsu, Akira Yamauchi, Masahiro Yamamura, Kumiko Terada, Masumi Itadani, Naoko Okada, Nur Mohammad Monsur Hassan, Hitoshi Nagatsuka, Tohru Ikeda, Tsutomu Nohno, Shuichi Fujita

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.

Original languageEnglish
Pages (from-to)45-58
Number of pages14
JournalOncology Research
Volume26
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Wnt Signaling Pathway
Neoplasms
Cell Proliferation
Phosphatidylinositol 3-Kinases
Western Blotting
Cell Line
Catenins
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Carcinoma, squamous cell of head and neck
Cyclin D1
Microarray Analysis
Esophageal Neoplasms
Pancreatic Neoplasms
Small Interfering RNA
Stomach Neoplasms
Cell Movement
Transfection
Colorectal Neoplasms
Lung Neoplasms
Prostatic Neoplasms

Keywords

  • DKK3
  • Head and neck squamous cell carcinoma (HNSCC)
  • Oral cancer
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Katase, N., Nishimatsu, S. I., Yamauchi, A., Yamamura, M., Terada, K., Itadani, M., ... Fujita, S. (2018). DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells. Oncology Research, 26(1), 45-58. https://doi.org/10.3727/096504017X149268745963860965-0407

DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells. / Katase, Naoki; Nishimatsu, Shin Ichiro; Yamauchi, Akira; Yamamura, Masahiro; Terada, Kumiko; Itadani, Masumi; Okada, Naoko; Hassan, Nur Mohammad Monsur; Nagatsuka, Hitoshi; Ikeda, Tohru; Nohno, Tsutomu; Fujita, Shuichi.

In: Oncology Research, Vol. 26, No. 1, 01.01.2018, p. 45-58.

Research output: Contribution to journalArticle

Katase, N, Nishimatsu, SI, Yamauchi, A, Yamamura, M, Terada, K, Itadani, M, Okada, N, Hassan, NMM, Nagatsuka, H, Ikeda, T, Nohno, T & Fujita, S 2018, 'DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells', Oncology Research, vol. 26, no. 1, pp. 45-58. https://doi.org/10.3727/096504017X149268745963860965-0407
Katase, Naoki ; Nishimatsu, Shin Ichiro ; Yamauchi, Akira ; Yamamura, Masahiro ; Terada, Kumiko ; Itadani, Masumi ; Okada, Naoko ; Hassan, Nur Mohammad Monsur ; Nagatsuka, Hitoshi ; Ikeda, Tohru ; Nohno, Tsutomu ; Fujita, Shuichi. / DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells. In: Oncology Research. 2018 ; Vol. 26, No. 1. pp. 45-58.
@article{b5be15f34bd742d69267f0faeed6410d,
title = "DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells",
abstract = "DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.",
keywords = "DKK3, Head and neck squamous cell carcinoma (HNSCC), Oral cancer, Wnt signaling",
author = "Naoki Katase and Nishimatsu, {Shin Ichiro} and Akira Yamauchi and Masahiro Yamamura and Kumiko Terada and Masumi Itadani and Naoko Okada and Hassan, {Nur Mohammad Monsur} and Hitoshi Nagatsuka and Tohru Ikeda and Tsutomu Nohno and Shuichi Fujita",
year = "2018",
month = "1",
day = "1",
doi = "10.3727/096504017X149268745963860965-0407",
language = "English",
volume = "26",
pages = "45--58",
journal = "Oncology Research",
issn = "0965-0407",
publisher = "Cognizant Communication Corporation",
number = "1",

}

TY - JOUR

T1 - DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells

AU - Katase, Naoki

AU - Nishimatsu, Shin Ichiro

AU - Yamauchi, Akira

AU - Yamamura, Masahiro

AU - Terada, Kumiko

AU - Itadani, Masumi

AU - Okada, Naoko

AU - Hassan, Nur Mohammad Monsur

AU - Nagatsuka, Hitoshi

AU - Ikeda, Tohru

AU - Nohno, Tsutomu

AU - Fujita, Shuichi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.

AB - DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.

KW - DKK3

KW - Head and neck squamous cell carcinoma (HNSCC)

KW - Oral cancer

KW - Wnt signaling

UR - http://www.scopus.com/inward/record.url?scp=85040555534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040555534&partnerID=8YFLogxK

U2 - 10.3727/096504017X149268745963860965-0407

DO - 10.3727/096504017X149268745963860965-0407

M3 - Article

C2 - 28470144

AN - SCOPUS:85040555534

VL - 26

SP - 45

EP - 58

JO - Oncology Research

JF - Oncology Research

SN - 0965-0407

IS - 1

ER -