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RAB11A Expression Is Associated With Cancer Aggressiveness Through Regulation of FGFR-Signaling in Lung Squamous Cell Carcinoma

  • Translational Research
  • Published:
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Abstract

Background

Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling.

Methods

Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo.

Results

The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells.

Conclusion

As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.

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Acknowledgments

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science JSPS 21K16526 (to Yoko Azuma) and Gunma University Women Researcher Grant (to Gombodorj Navchaa). The authors thank Dr. Akira Iyoda, Dr. Toshihide Kato, Ms. Yukiko Sutou, and Mr. Koji Isoda for their excellent assistance.

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Author notes

  1. Navchaa Gombodorj and Yoko Azuma contributed equally to this article.

Authors and Affiliations

  1. Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

    Navchaa Gombodorj MD, PhD & Takehiko Yokobori MD, PhD

  2. Department of Radiation Oncology, National Cancer Center, Ulaanbaatar, Mongolia

    Navchaa Gombodorj MD, PhD

  3. Division of Chest Surgery, Department of Surgery, Toho University School of Medicine, Tokyo, Japan

    Yoko Azuma MD, PhD

  4. Departments of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

    Bilguun Erkhem-Ochir MD, PhD, Takayuki Kosaka MD, PhD, Yoichi Ohtaki MD, PhD, Seshiru Nakazawa MD, PhD, Akira Mogi MD, PhD, Toshiki Yajima MD, PhD, Hiroyuki Kuwano MD, PhD, Hiroshi Saeki MD, PhD & Ken Shirabe MD, PhD

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  1. Navchaa Gombodorj MD, PhD
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  2. Yoko Azuma MD, PhD
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  3. Takehiko Yokobori MD, PhD
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Corresponding author

Correspondence to Takehiko Yokobori MD, PhD.

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Disclosures

There are no conflicts of interest.

Ethical Approval

The establishment of tissue sample from surgically resected LSCC tissues was approved by the Institutional Review Board of Gunma University (approval no. HS2020-086). Patient consent was obtained using the opt-out method. All mouse experiments were conducted in compliance with the guidelines of the Institute for Laboratory Animal Research at Gunma University, Maebashi, Japan.

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The study was performed in accordance with the Declaration of Helsinki.

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Supplementary Information

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10434_2022_11833_MOESM1_ESM.pdf

Re-analysis of public microarray data for 130 cases of lung squamous cell carcinoma (LSCC). A microarray dataset of 130 primary LSCC specimens was re-analyzed (GSE4573: Raponi M, et al.10).<AQ13> The gene expression was compared between patients with a survival interval shorter than 2 years after surgery and patients with a survival interval longer than 5 years after surgery in the LSCC cohort to identify biomarkers of poor prognosis for LSCC. The re-analysis identified RAB11A, RNF128, PPME1, GPR157, and PKM2 as putative biomarkers and candidate therapeutic genes for the poor prognosis of LSCC. Of these, the study focused on the RAB11A as a new therapeutic candidate because the high expression of RAB11A was associated with the highest relative risk for overall survival. Receiver operating characteristic (ROC) curve analyses were used to evaluate the potential of the candidate genes as prognostic markers. These statistical analyses were performed using JMP software (SAS Institute, Inc. Albany, NY, USA) (PDF 59 kb)

10434_2022_11833_MOESM2_ESM.pdf

Kaplan-Meier curves for lung squamous cell carcinoma (LSCC) patients with stage 1 disease according to the level of RAB11A expression. Overall survival curves are shown for LSCC patients with stage 1 disease (n = 51) based on the level of cytoplasm RAB11A expression (P = 0.0159) (PDF 25 kb)

10434_2022_11833_MOESM3_ESM.pdf

RAB11A and fibroblast growth factor receptor 1 (FGFR1) expression overlapped in lung squamous cell carcinoma (LSCC) tumors, not in normal lung tissue. Multicolor fluorescent immunostaining of RAB11A (purple), FGFR1 (green), and phospho-FGFR (red) is shown. Nuclei are stained blue with DAPI. Scale bars indicate 50 µm. T, tumor; N, normal lung tissue (PDF 439 kb)

10434_2022_11833_MOESM4_ESM.pdf

Combination effects of the RAB11A targeting, the fibroblast growth factor receptor (FGFR) inhibitor nintedanib, and cisplatin (CDDP) on RAB11A-suppressed lung squamous cell carcinoma (LSCC) cells. Cytotoxic effects were measured by the percentage of cell viability at different doses of drug. The RAB11A-suppressed EBC-1 and HCC15 cells were treated with potent, multi-targeted tyrosine kinase inhibitors including FGFRs, nintedanib, and the cytotoxic agent, CDDP. Cell viability was evaluated using Cell-Counting Kit-8 (CCK-8) assays after 72 h of drug treatment (PDF 98 kb)

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Gombodorj, N., Azuma, Y., Yokobori, T. et al. RAB11A Expression Is Associated With Cancer Aggressiveness Through Regulation of FGFR-Signaling in Lung Squamous Cell Carcinoma. Ann Surg Oncol 29, 7149–7162 (2022). https://doi.org/10.1245/s10434-022-11833-5

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  • DOI: https://doi.org/10.1245/s10434-022-11833-5

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