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REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Objectives

Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation plus TTF-1 low expression (KC subgroup). The aim of this study was to identify valuable biomarkers by searching the candidate molecules that contribute to lung adenocarcinoma pathogenesis, especially KC subtype.

Materials and methods

We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after silencing the REG4 expression.

Results

REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutant lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduces cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce cell cycle arrest by regulating G2/M checkpoint and E2F targets.

Conclusion

Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanisms of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.

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Funding

This work was supported by a grant from the National Natural Science Foundation for Young Scientists [Grant number 81501965, Dr. Hui Yu].

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Author notes

  1. Si Sun and Zhihuang Hu contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China

    Si Sun, Zhihuang Hu, Jialei Wang, Jianhua Chang, Xianghua Wu, Lanlin Zhang & Hui Yu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Si Sun, Zhihuang Hu, Jialei Wang, Jianhua Chang, Xianghua Wu, Qifeng Wang, Lanlin Zhang & Hui Yu

  3. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Shenglin Huang

  4. Gracell Biotech Co. Ltd, Shanghai, 200233, China

    Xun Ye

  5. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Qifeng Wang

  6. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Research Center for Clinical Pharmacy, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China

    Xingjiang Hu

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  1. Si Sun
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Corresponding authors

Correspondence to Xingjiang Hu or Hui Yu.

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The authors declare no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center and carried out in accordance with the 1964 Helsinki declaration and its later amendments. All patients provided written informed consent before any study-related procedure. All animal studies were manipulated using protocols approved by the Shanghai Medical Experimental Animal Care Commission.

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Sun, S., Hu, Z., Huang, S. et al. REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression. J Cancer Res Clin Oncol 145, 2273–2283 (2019). https://doi.org/10.1007/s00432-019-02988-y

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  • DOI: https://doi.org/10.1007/s00432-019-02988-y

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