BTNL9 exerts anti-cancer effects by inhibiting CDC20 to induce G2/M arrest in pancreatic cancer.

Abstract

Background: Pancreatic cancer (PC) is an aggressive malignancy. As a member of the BTN/BTNL family, BTNL9 has been identified as a tumor suppressor in breast cancer, lung adenocarcinoma, and colon cancer; however, its role and underlying mechanisms in PC remain to be elucidated.

Aim: To investigate the role of BTNL9 in the pathogenesis and development of PC.

Methods: The difference of BTNL9 expression in cancer and adjacent normal tissues was analyzed by RNA sequencing data from a public database and tissue microarray detection. The relationship between BTNL9 expression and the prognosis of patients was also studied. The effects of BTNL9 on proliferation, metastasis, and cell cycle of PC cells were investigated by phenotypic experiments. The mechanism was investigated by RNA sequencing, western blotting, and immunofluorescence detection.

Results: The mRNA and protein levels of BTNL9 in PC tissues were downregulated compared with normal tissues. Based on survival data from The Cancer Genome Atlas and tissue microarray, BTNL9 was an independent influencing factor for overall survival, and its low expression predicted a shortened overall survival of patients. In vitro, BTNL9 could inhibit cell proliferation and metastasis in both PANC-1 and MIA PaCa-2 cells and induce cell cycle arrest in G2/M phases. Downregulation of BTNL9 could activate the cell cycle signaling pathway. Furthermore, overexpression of BTNL9 could significantly inhibit the expression of cell division cycle 20 (CDC20). Rescue experiments demonstrated that overexpression of CDC20 reversed the effect of BTNL9 on the proliferation, metastasis, and cell cycle of PC cells.

Conclusion: The expression of BTNL9 was downregulated in PC, and it has the prediction ability for prognosis. Functionally, BTNL9 exerted an anti-cancer effect by suppressing downstream CDC20 expression in PC.