An alpha-kinase 2 gene variant disrupts filamentous actin localization in the surface cells of colorectal cancer spheroids

Kensuke Nishi, Hao Luo, Kazuhiko Nakabayashi, Keiko Doi, Shuhei Ishikura, Yuri Iwaihara, Yasuhiro Yoshida, Kumpei Tanisawa, Tomio Arai, Seijiro Mori, Motoji Sawabe, Masaaki Muramatsu, Masashi Tanaka, Toshifumi Sakata, Senji Shirasawa, Toshiyuki Tsunoda

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background/Aim: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene downregulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. Materials and Methods: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). Results: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. Conclusion: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.

Original languageEnglish
Pages (from-to)3855-3862
Number of pages8
JournalAnticancer Research
Volume37
Issue number7
DOIs
Publication statusPublished - 2017 Jul 1
Externally publishedYes

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Actins
Colorectal Neoplasms
Phosphotransferases
Genes
Apoptosis
Amino Acids
Neoplasms
Cell Aggregation
Tumor Suppressor Genes
Population
Autopsy
Exons
Down-Regulation
Nucleotides
Cell Culture Techniques
Odds Ratio
Confidence Intervals
Phenotype

Keywords

  • ALPK2
  • Basolateral polarity
  • Colorectal cancer
  • Intercellular interaction
  • Luminal apoptosis
  • Missense variation
  • Three-dimensional floating culture

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

An alpha-kinase 2 gene variant disrupts filamentous actin localization in the surface cells of colorectal cancer spheroids. / Nishi, Kensuke; Luo, Hao; Nakabayashi, Kazuhiko; Doi, Keiko; Ishikura, Shuhei; Iwaihara, Yuri; Yoshida, Yasuhiro; Tanisawa, Kumpei; Arai, Tomio; Mori, Seijiro; Sawabe, Motoji; Muramatsu, Masaaki; Tanaka, Masashi; Sakata, Toshifumi; Shirasawa, Senji; Tsunoda, Toshiyuki.

In: Anticancer Research, Vol. 37, No. 7, 01.07.2017, p. 3855-3862.

Research output: Contribution to journalArticle

Nishi, K, Luo, H, Nakabayashi, K, Doi, K, Ishikura, S, Iwaihara, Y, Yoshida, Y, Tanisawa, K, Arai, T, Mori, S, Sawabe, M, Muramatsu, M, Tanaka, M, Sakata, T, Shirasawa, S & Tsunoda, T 2017, 'An alpha-kinase 2 gene variant disrupts filamentous actin localization in the surface cells of colorectal cancer spheroids', Anticancer Research, vol. 37, no. 7, pp. 3855-3862. https://doi.org/10.21873/anticanres.11765
Nishi, Kensuke ; Luo, Hao ; Nakabayashi, Kazuhiko ; Doi, Keiko ; Ishikura, Shuhei ; Iwaihara, Yuri ; Yoshida, Yasuhiro ; Tanisawa, Kumpei ; Arai, Tomio ; Mori, Seijiro ; Sawabe, Motoji ; Muramatsu, Masaaki ; Tanaka, Masashi ; Sakata, Toshifumi ; Shirasawa, Senji ; Tsunoda, Toshiyuki. / An alpha-kinase 2 gene variant disrupts filamentous actin localization in the surface cells of colorectal cancer spheroids. In: Anticancer Research. 2017 ; Vol. 37, No. 7. pp. 3855-3862.
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abstract = "Background/Aim: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene downregulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. Materials and Methods: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). Results: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95{\%} confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. Conclusion: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.",
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AU - Nishi, Kensuke

AU - Luo, Hao

AU - Nakabayashi, Kazuhiko

AU - Doi, Keiko

AU - Ishikura, Shuhei

AU - Iwaihara, Yuri

AU - Yoshida, Yasuhiro

AU - Tanisawa, Kumpei

AU - Arai, Tomio

AU - Mori, Seijiro

AU - Sawabe, Motoji

AU - Muramatsu, Masaaki

AU - Tanaka, Masashi

AU - Sakata, Toshifumi

AU - Shirasawa, Senji

AU - Tsunoda, Toshiyuki

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N2 - Background/Aim: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene downregulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. Materials and Methods: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). Results: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. Conclusion: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.

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