Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells

Mengyi Lao,Xiaoyu Zhang,Jian Xu,Xiaozhen Zhang,Tingbo Liang,Hanshen Yang,Xueli Bai,Junyu Qiu,Tao Ma,Chengxiang Guo,Honggang Ying,Yi Duan

doi:10.1038/s41388-021-01763-z

Abstract

Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a serious malignancy whose prognosis is very poor
RCAN1.4 is a candidate tumor suppressor that is associated with poor prognosis in patients with pancreatic cancer
We found that RCAN1.4 levels were reduced significantly in PDAC tissues compared with those in paracancerous tissues (Fig. 1A, B)

Summary

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Pancreatic ductal adenocarcinoma (PDAC) is a serious malignancy whose prognosis is very poor. Lee et al demonstrated that in Pdx-1Cre;LSL-KrasG12D mice, a genetically engineered mouse model of human PDAC, RCAN1 trisomy could suppress the progression of early pancreatic intraepithelial neoplasia lesions by attenuating the calcineurin-nuclear localization of nuclear factor of activated T cells (NFAT) axis, together with inhibition of cell proliferation in the neoplastic ductal epithelium [14]. TCGA analysis showed that RCAN1.4 was the major RCAN1 isoform in the PDAC tissues based on the median TPM value, and RCAN1.1 and RCAN1.2, were found at low levels (Fig. 1E). Kaplan–Meier survival analysis showed that patients with PDAC with low RCAN1.4 protein levels had worse overall survival (OS) than those with high RCAN1.4 protein levels, as analyzed using the tumor microarray (Fig. 1F, G). Similarity, TCGA analysis showed the mRNA levels of RCAN1 were no significantly associated with grade and TNM stage (Supplementary Fig. 1A, B). Our results indicated that RCAN1.4 is a tumor suppressor that is associated with poor prognosis in patients with pancreatic cancer

Results

Discussion

Materials and methods

Compliance with ethical standards