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. 2022 Dec 12;10(12):3225.
doi: 10.3390/biomedicines10123225.

Comparing TIMP-1 and Hsp70 in Blood and Saliva as Potential Prognostic Markers in HNSCC

Jakob Rinecker  1 , Romina Roesch  2 , Sara Krippgans  3 , Markus Nieberler  3 , Leonhard Stark  1 , Stefan Stangl  4 , Bernhard Haller  5 , Kristin Fritsche  6 , Gabriele Multhoff  4 , Andreas Knopf  7 , Christof Winter  2 , Barbara Wollenberg  1 , Markus Wirth  1
Affiliations

Comparing TIMP-1 and Hsp70 in Blood and Saliva as Potential Prognostic Markers in HNSCC

Jakob Rinecker et al. Biomedicines. .

Abstract

(1) Background: Currently, there is no clinically used liquid biomarker in head and neck squamous cell carcinoma (HNSCC) patients. One reason could be the limited shedding of tumor material in early disease stages. Molecular diagnostics assessing both blood and especially saliva could potentially improve the accuracy of biomarkers. In this prospective study, two markers, tissue inhibitor of metalloprotease-1 (TIMP-1) and heat shock protein 70 (Hsp70), were analyzed in HNSCC patients. The purpose of the study was to evaluate differences between saliva and serum as sample material. Further, their prognostic and predictive value and usefulness for early detection was assessed. (2) Methods: A total of 73 HNSCC patients were prospectively monitored by collecting blood and saliva before, during, and after therapy, as well as in the follow-up period between 2018 and 2021. In total, 212 serum and 194 saliva samples were collected. A control group consisting of 40 subjects (15 patients with local infections in the head and neck area and 25 without infections) were examined as well. The collected samples were evaluated for the two proteins by using an enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: The TIMP-1 concentration correlated significantly in blood and saliva, whereas the Hsp70 concentration did not. Saliva TIMP-1 was significantly higher in tumor patients compared to the control group (p = 0.013). High pretreatment TIMP-1 saliva levels were associated with significantly poorer disease-free survival (DFS) (p = 0.02). A high saliva TIMP-1/Hsp70 ratio was significantly associated with poorer DFS (HR: 1.4; 95% CI: 1.04-1.88; p = 0.026) and a high TIMP-1 serum concentration was significantly associated with poorer PFS (HR: 1.9; 95% CI: 1.2, 2.8; p = 0.003) and poorer overall survival (OS) (HR: 2.9; 95% CI: 1.4, 5.9; p = 0.003) in the Cox proportional hazards model. The saliva TIMP-1 to Hsp70 ratio was significantly higher at the time of recurrence (p = 0.015). Conclusion: TIMP-1 in serum is a promising prognostic marker for HNSCC. Saliva TIMP-1 and the saliva TIMP-1 to Hsp70 ratio provides additional information on the disease-free survival.

Keywords: HNSCC; Hsp70; TIMP-1; saliva.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Number of HNSCC patients (total n = 73) with one or more sample collections at different timepoints of treatment and follow-up. The size of the bar represents the number of patients at a timepoint. Lines between the bars represent patients with both timepoints in the study timeline.
Figure 2
Figure 2
(a) TIMP-1 saliva concentration in subjects with HNSCC, control subjects without infection, and control subjects with head and neck infection; (b) TIMP-1 serum concentration in subjects with HNSCC, control subjects without infection, and control subjects with head and neck infection; (c) Hsp70 saliva concentration in subjects with HNSCC, control subjects without infection, and control subjects with head and neck infection; and (d) Hsp70 serum concentration in subjects with HNSCC, control subjects without infection, and control subjects with head and neck infection.
Figure 3
Figure 3
Comparing pretreatment HNSCC (n = 53) and combined control subjects (n = 40) for TIMP-1 and Hsp70 both in serum and saliva. (a) TIMP-1 saliva concentration in HNSCC and combined control subjects; (b) Hsp70 saliva concentration in HNSCC and combined control subjects; (c) TIMP-1/Hsp70 saliva ratio comparing HNSCC and combined control subjects; (d) saliva TIMP-1 in smokers with HNSCC and combined smoking control subjects; (e) saliva Hsp70 in smokers with HNSCC and combined smoking control subjects; and (f) TIMP-1/Hsp70 ratio in smokers with HNSCC and combined smoking control subjects.
Figure 4
Figure 4
(a) Disease-free survival probability for high and low saliva TIMP-1 by the median cut-off of 62.8 ng; (b) comparison of saliva Hsp70 during follow-up (mean per subject) for HNSCC-patients without recurrence, before recurrence, and levels at the time of recurrence; (c) comparison of saliva TIMP-1 during follow-up (mean per subject) for HNSCC-patients without recurrence, before recurrence, and levels at the time of recurrence; and (d) comparison of saliva TIMP-1/Hsp70 ratio during follow-up (mean per subject) for HNSCC patients without recurrence, before recurrence, and levels at the time of recurrence).
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