CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors

Abstract

Although the postoperative recurrence rate for pancreatic neuroendocrine tumors (PNETs) is reported to be 13.5%‐30%, the paucity of valuable biomarkers to predict recurrence poses a problem for the early detection of relapse. Hence, this study aimed to identify new biomarkers to predict the recurrence of PNETs. We performed RNA sequencing (RNA‐Seq) on RNA isolated from frozen primary tumors sampled from all localized G1/G2 PNETs resected curatively from 1998 to 2015 in our institution. We calculated differentially expressed genes (DEGs) in tumor with and without recurrence (≥3 years) for the propensity‐matched cohort. Gene ontology analysis for the identified DEGs was also performed. Furthermore, we evaluated the expression levels of candidate genes as recurrence predictors via immunostaining. Comparison of transcriptional levels in tumors with and without recurrence identified 166 DEGs. Up‐ and downregulated genes with high significance in these tumors were mainly related to extracellular organization and cell adhesion, respectively. We observed the top three upregulated genes, C‐type lectin domain family 3 member A (CLEC3A), matrix metalloproteinase‐7 (MMP7), and lipocalin2 (LCN2) immunohistochemically and compared their levels in recurrent and nonrecurrent tumors. Significantly higher recurrence rate was shown in patients with positive expression of CLEC3A ( P = 0.028), MMP7 ( P = 0.003), and LCN2 ( P = 0.040) than that with negative expression. We identified CLEC3A, MMP7, and LCN2 known to be associated with the phosphatidylinositol‐3‐kinase/Akt pathway, as potential novel markers to predict the postoperative recurrence of PNETs.

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

“…In this study, we identified LCN2 as a potential regulator of vitamin D. LCN2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is a tumour- This finding was validated with our laboratory findings, clarifying that LCN2 is a tumour chemosensitive gene and has potential as a predictor of tumour recurrence 31 . Furthermore, we experimentally proved that the regulation of LCN2 and VDR genes is independent of each other.…”

“…Quantitative methylation-specific PCR (qMSP) was performed as described previously 31 . Briefly, genomic DNA was isolated with a Genomic DNA Purification Kit (Thermo Fisher Scientific, Cat.…”

Prognosis analysis of patients with pancreatic neuroendocrine tumors after surgical resection and the application of enucleation

“…pNET patients with G3, distant metastasis, larger tumor diameter, AJCC 8th III-IV stage, the white race, or age > 60 years old were associated with a worse OS/CSS. A higher pathological grade and lower differentiation of tumor cells indicate the tumor may be more malignant [ 13 , 14 ], some pNET patients with distant metastasis are difficult to treat since the removal of the primary and metastatic tumors may be impossible, and most of them can only achieve R1 or R2 resection [ 8 ]. Their prognosis is poorer than patients with an R0 resection.…”

Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

“…LCN2 has been implicated in the progression of several types of human tumors. LCN2 expression is higher in solid tumors than in corresponding normal tissues [24,41], and it is mainly described as tumor promoter in many cancers, including pancreas, glioblastoma, thyroid, kidney, esophagus, and breast cancer [20,28,[42][43][44][45][46][47][48].…”