Diagnostic utility of trefoil factor families for the early detection of lung cancer and their correlation with tissue expression

Kentaro Minegishi; Yoh Dobashi; Teruhide Koyama; Yuko Ishibashi; Miki Furuya; Hiroyoshi Tsubochi; Yasukazu Ohmoto; Tomohiko Yasuda; Sachiyo Nomura

doi:10.3892/ol.2023.13725

Diagnostic utility of trefoil factor families for the early detection of lung cancer and their correlation with tissue expression

Oncol Lett. 2023 Feb 21;25(4):139. doi: 10.3892/ol.2023.13725. eCollection 2023 Apr.

Authors

Kentaro Minegishi¹, Yoh Dobashi^{2

3}, Teruhide Koyama⁴, Yuko Ishibashi⁵, Miki Furuya⁶, Hiroyoshi Tsubochi¹, Yasukazu Ohmoto⁷, Tomohiko Yasuda^{6

8}, Sachiyo Nomura⁶

Affiliations

¹ Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8500, Japan.
² Department of Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8500, Japan.
³ Department of Pathology, School of Medicine, International University of Health and Welfare Hospital, Nasushiobara, Tochigi 329-2763, Japan.
⁴ Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan.
⁵ Department of Surgery, Breast Surgery, Tokyo Women's Medical University, Adachi Medical Center, Adachi, Tokyo 123-8558, Japan.
⁶ Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁷ Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Tokushima 770-8505, Japan.
⁸ Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba 270-1694, Japan.

Abstract

Trefoil factors (TFFs) are upregulated in numerous types of cancer, including those of the breast, the colon, the lung and the pancreas, suggesting their potential utility as biomarkers for screening. In the present study, the clinical relevance of serum or urinary TFFs as biomarkers were comprehensively evaluated and the correlation with TFF expression levels in lung cancer tissue was examined. Serum and urine were collected from 199 patients with lung cancer and 198 healthy individuals. Concentrations of serum and urinary TFF1, TFF2 and TFF3 were measured using ELISA and the potential of TFF levels to discriminate between cancer and non-cancer samples was evaluated. In 100 of the cancer cases, expression of TFF1-3 was analyzed using immunohistochemical staining of paraffin sections. Furthermore, the relationship between TFF levels and clinicopathological factors among these cancer cases was analyzed using immunohistochemistry of tissue specimens, quantified and statistically analyzed. While serum levels of all TFFs measured using ELISA were significantly higher in patients with lung cancer compared with those in healthy individuals, urinary TFFs were lower. Areas under the curve (AUC) of the receiver operating characteristic curves for serum/urinary TFF1, TFF2 and TFF3 were 0.709/0.594, 0.722/0.501 and 0.663/0.665, respectively. Furthermore, the combination of serum TFF1, TFF2, TFF3 and urinary TFF1 and TFF3 demonstrated the highest AUC (0.826). In the clinicopathological analysis, serum TFF1 was higher in the early pathological T-stage (pTis/1/2) compared with the later stage (pT3/4) and TFF2 was higher in the pN0/1 than the pN2 group. With regards to the histological types, urinary TFF1 was higher in squamous cell carcinoma than adenocarcinoma (AC), but TFF2 tended to be higher in AC. Using immunohistochemical analysis, although TFF1 and TFF3 expression showed positive correlation with serum concentrations, TFF2 was inversely correlated. In conclusion, serum and urinary TFF levels are promising predictive biomarkers, and their measurements provide a useful in vivo and non-invasive diagnostic screening tool. In particular, TFF1 and TFF3 could be surrogate markers of clinicopathological profiles of human lung cancer.

Keywords: ELISA; TFF; biomarker; immunohistochemistry; lung carcinoma.

Grants and funding

This work was partially supported by the Japan Society for the Promotion of Science (grant no. 17K08727, 20K07378, 16H06277, 22H04923 and 23501295), Grants-in-Aid for Scientific Research for Priority Areas of Cancer (grant no. 17015018), Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant nos. 221S0001, Ca180066, Ca190058, Ca200066 and Ca210033), the Smoking Research Foundation and the Princess Takamatsu Cancer Research Fund.