Pancreatic　cancer　(PC)　is　one　of　the　most　aggressive　and　devastating　types　of　cancer　owing　to　its　poor　prognosis　and　deadly　characteristics.　It　is　well　established　that　aberrations　in　the　expression　of　key　regulatory　genes,　namely　tumor　suppressors　and　oncogenes,　predispose　patients　to　progression　and　metastasis　of　PC.　Upregulation　of　Williams-Beuren　syndrome　chromosomal　region　22　(WBSCR22)　expression,　a　ribosomal　biogenesis　factor,　has　been　reported　in　multiple　types　of　human　cancer.　However,　the　role　of　WBSCR22　and　its　underlying　mechanism　in　PC　have　not　been　well　investigated.　In　the　present　study,　the　tumor　suppressive　role　of　WBSCR22　was　reported　in　PC　for　the　first　time;　the　results　indicated　that　WBSCR22　overexpression　(OE)　significantly　suppressed　cellular　proliferation,　migration,　invasion　and　tumorigenesis　in　vivo　and　in　vitro.　RNA-sequencing　analysis　revealed　that　WBSCR22　negatively　regulated　the　transcription　of　interferon-stimulated　gene　15　(ISG15)　downstream,　which　is　a　ubiquitin-like　modifier　protein　involved　in　metabolic　and　proteasome　degradation　pathways,　while　the　antitumor　function　of　WBSCR22-OE　could　be　rescued　by　ISG15　OE.　In　addition,　the　oncogenic　role　of　ISG15　was　further　confirmed　in　PC;　its　upregulation　promoted　the　proliferation,　migration,　invasion　and　tumorigenesis　of　PC.　Furthermore,　WBSCR22　and　its　cofactor　tRNA　methyltransferase　activator　subunit　11-2　(TRMT112)　functioned　synergistically　in　PC,　and　concurrent　ectopic　OE　of　WBSCR22　and　TRMT112　further　promoted　the　tumor　suppressive　potential　of　WBSCR22　in　PC.　Collectively,　the　findings　indicated　that　WBSCR22　played　an　important　role　in　PC　development　and　that　the　WBSCR22/ISG15　axis　may　provide　a　novel　therapeutic　strategy　for　PC　treatment.