Annexin A8 Is a Prognostic Marker and Potential Therapeutic Target for Pancreatic Cancer

Abstract

Objectives We investigated whether annexin-A8 (A-A8), a Ca2+-binding protein overexpressed in pancreatic cancer, plays a role in cell growth and migration, and its association with pancreatic cancer prognosis. Methods Clinicopathological features and associations between increased A-A8 expression (determined by immunohistochemistry) and histologic grade were studied in a tissue microarray of 90 resected stage I/II pancreatic cancer patients. We investigated A-A8’s effect on cell migration, proliferation, and colony formation in 2 pancreatic cancer cells (BXPC-3, Panc-1). Statistical analyses included Fisher’s exact test, t-test, ANOVA, and survival analysis. Results Western blot showed increased A-A8 expression in human pancreatic cancer cells, with A-A8 knockdown in BXPC-3 and Panc-1 cells demonstrating decreased cell viability (P=0.017, P=0.001), migration (2.5 vs. 0.9 and 1.6 vs. 1 mm at 96 h; P=0.048, P=0.004), and colony formation (~75% and 40% from scramble; P≤0.01), respectively. In our tissue microarray, A-A8 expression increased 5.9-fold (r=0.31; P=0.019) from low- to high-grade tumors, correlating with tumor grade (r=0.23; P=0.027). Additionally, high A-A8 expression was associated with decreased 5-year survival (P=0.042). Conclusion Our study is the first showing increased A-A8 expression is associated with poor prognosis in early stage pancreatic cancer; thus supporting further investigation as a future therapeutic target and prognostic marker.

Annexin A8 regulated by lncRNA-TUG1/miR-140-3p axis promotes bladder cancer progression and metastasis

“… 40 Previous studies have confirmed high expression of ANXA8 and its prognostic role in acute promyelocytic leukemia, high-grade breast cancer, pancreatic cancer, and ovarian cancer. 8 , 9 , 10 , 11 For instance, prognostic analysis has revealed that high expression of ANXA8 is closely associated with poor prognosis in ovarian cancer. 11 However, the function and miRNA-mediated mechanisms of ANXA8 in bladder cancer remain poorly understood.…”

“… 5 , 6 Annexin A8 ( ANXA8 ) was first discovered as an anticoagulation factor, 7 and growing evidence has illustrated that ANXA8 is elevated in various types of cancers, including pancreatic cancer, breast cancer, acute promyelocytic leukemia, and ovarian cancer. 8 , 9 , 10 , 11 As reported, upregulated ANXA8 in pancreatic cancer is positively correlated with tumor grade and decreased 5-year survival, and knockdown of ANXA8 impairs cell viability in pancreatic cancer cells, 10 indicating its oncogenic role in pancreatic cancer. However, the biological roles of ANXA8 and its relevant mechanisms in bladder cancer remain elusive.…”

Prognostic Value of ANXA8 in Gastric Carcinoma

“…Of note, ANXA8 is crucial in the maintenance of the late endosomal/lysosomal compartment physiological functions in cancer cells [16] and is able to interact with phosphatidylinositides and actin-associated membrane domains [25] which are closely related to cell migration, cytokinesis, vesicle transport and cellular immunity. It has also been clarified that high expression of ANXA8 in pancreatic cancer [20][21][22] and ovarian cancer [23] was correlated with tumor cell invasion and proliferation. ANXA8 transcription is down-regulated by EGFR and its downstream targets, phosphatidylinositol-3-kinase and Akt, are universally known as key factors of tumors proliferation, migration and metastasis [24].…”

“…Meanwhile, ANXA8 has also been linked to the formation of endosomes and epidermal growth factor receptor (EGFR) turnover in Hela cells [16]. Other reports demonstrated that the expression of ANXA8 is significantly increased in breast cancer [17][18][19], pancreatic cancer [20][21][22], ovarian cancer [23] and cholangiocarcinoma [24]. Thus, ANXA8 is expected to be a new biomarker and molecular therapeutic target for the diagnosis, treatments and prognosis of multiple diseases, especially malignant tumors.…”

Emerging Cancer Epigenetic Mechanisms Regulated by All-Trans Retinoic Acid

“…A pancreatic cancer study speculated that ANXA8 expression was low in a normal pancreas due to CpG hypermethylation of the ANXA8 promoter-exon 1 region, while demethylation of the ANXA8 promoter-exon 1 region induced ANXA8 upregulation in pancreatic cancer that invaded the surrounding tissue and metastasized [ 149 ]. Increased ANXA8 expression was associated with a poor prognosis [ 150 ]. Mechanistic studies showed that in pancreatic ductal adenocarcinoma (PDAC), ANXA8 upregulation was induced by the zinc finger regulator ZIC2, which is a member of the ZIC gene family that associates with GLI transcription factors of Hedgehog signaling [ 148 , 149 , 151 , 152 ].…”