Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer

Abstract

Background

In recent years, systemic chemotherapy has significantly improved the prognosis of metastatic colorectal cancer (CRC); however, different patients have different responses to chemotherapeutics.

Methods

Dipeptidyl peptidase 9 (DPP9) is an enzyme in the dipeptidyl peptidase IV family that has been reported to increase drug sensitivity in acute myeloid leukemia. In this study, we examined the relationship between DPP9 expression and the prognosis of patients with CRC, as well as the role of DPP9 in anticancer drug resistance. Moreover, the effects of the DPP9 inhibitors talabostat and vildagliptin in CRC cell lines and primary cultured cells were assessed.

Results

High expression of DPP9 was associated with worse prognosis in 196 patients with CRC. Cell viability was markedly inhibited in CRC cell lines transfected with DPP9 small interfering RNA or small hairpin RNA. Talabostat suppressed proliferation in CRC cell lines and primary cultured cells, and increased their sensitivity to chemotherapy. Vildagliptin, a DPP family inhibitor currently administered for diabetes, also increased the sensitivity of CRC cells to anticancer drugs.

Conclusion

DPP9 was a poor prognostic factor for CRC and could be a new therapeutic target, while vildagliptin could be used as a repositioned drug for CRC treatment.

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Acknowledgment

The authors would like to thank Ms. Aya Ito for special technical assistance regarding sample preparation.

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Corresponding author

Correspondence to Norikatsu Miyoshi MD, PhD, FICS, FACS.

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Disclosure

Kazuhiro Saso, Norikatsu Myoshi, Shiki Fujino, Masaru Sasaki, Masayoshi Yasui, Masayuki Ohue, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki, and Hidetoshi Eguchi declare no competing financial interests.

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Supplementary Figure 1 Violin plots depicting the median DPP9/GAPDH ratio in 196 CRC patients based on stage. There were no significant differences based on stage (P = 0.940). DPP9, dipeptidyl peptidase 9; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; CRC: colorectal cancer (PNG 122 kb)

Supplementary Figure 2 Postoperative disease-free survival rates in patients with high and low DPP9 expression were not significantly different. DPP9, dipeptidyl peptidase 9; GAPDH; glyceraldehyde-3-phosphate dehydrogenase (PNG 153 kb)

Supplementary Figure 3 Overall survival based on DPP9 mRNA expression in CRC patients with postoperative recurrence. The 5-year OS was lower in patients with high DPP9 expression compared to those with low expression. DPP9, dipeptidyl peptidase 9; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; CRC, colorectal cancer; OS, overall survival (PNG 170 kb)

Supplementary Figure 4 DPP9 expression is increased in CRC and high expression is associated with worse overall survival in patients with adjuvant chemotherapy. In patient who were treated by adjuvant chemotherapy, the high-expression group had significantly lower 5-years OS than the low-expression group (P = 0.034), but there is no significant difference in disease-free survival between the two groups (P = 0.428). DPP9, dipeptidyl peptidase 9; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; CRC, colorectal cancer; OS, overall survival (PNG 103 kb)

Supplementary Figure 5 In patient who had recurrence and were treated by chemotherapy, the high-expression group had lower OS than the low-expression group (P = 0.067). DPP9, dipeptidyl peptidase 9; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; CRC: colorectal cancer; OS, overall survival (PNG 135 kb)

Supplementary material 6 (XLSX 9 kb)

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Saso, K., Miyoshi, N., Fujino, S. et al. Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer. Ann Surg Oncol 27, 4337–4347 (2020). https://doi.org/10.1245/s10434-020-08729-7

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