MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Better understanding of pancreatic cancer biology may help identify new oncotargets towards more effective therapies. This study investigated the mechanistic actions of microRNA-1291 (miR-1291) in the suppression of pancreatic tumorigenesis. Our data showed that miR-1291 was downregulated in a set of clinical pancreatic carcinoma specimens and human pancreatic cancer cell lines. Restoration of miR-1291 expression inhibited pancreatic cancer cell proliferation, which was associated with cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 sharply suppressed the tumorigenicity of PANC-1 cells in mouse models. A proteomic profiling study revealed 32 proteins altered over 2-fold in miR-1291-expressing PANC-1 cells that could be assembled into multiple critical pathways for cancer. Among them anterior gradient 2 (AGR2) was reduced to the greatest degree. Through computational and experimental studies we further identified that forkhead box protein A2 (FOXA2), a transcription factor governing AGR2 expression, was a direct target of miR-1291. These results connect miR-1291 to the FOXA2-AGR2 regulatory pathway in the suppression of pancreatic cancer cell proliferation and tumorigenesis, providing new insight into the development of miRNA-based therapy to combat pancreatic cancer.

Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models

“…Our recent studies have demonstrated that miR-1291 suppresses proliferation and tumorigenesis of PC cells [17]. To further delineate the molecular mechanisms through which miR-1291 controls PC cell growth, computational analysis was conducted to predict potential targets of miR-1291.…”

“…Furthermore, multiple miRNAs display tissue -specific aberrant expression in cancer development, suggesting the potential of developing miRNA based anticancer therapies besides serving as diagnostic or prognostic markers [12,13] including those for PC [14][15][16]. Recently, we have identified that miR-1291 is significantly downregulated in PC tissues compared with normal pancreatic tissues [17]. Our studies have also demonstrated that restoration of miR-1291 expression/function suppresses the proliferation, migration, invasion, and tumorigenesis of PC cells through the induction of apoptosis and cell cycle arrest, as well as alteration of PC cell metabolome [17,18].…”

“…Recently, we have identified that miR-1291 is significantly downregulated in PC tissues compared with normal pancreatic tissues [17]. Our studies have also demonstrated that restoration of miR-1291 expression/function suppresses the proliferation, migration, invasion, and tumorigenesis of PC cells through the induction of apoptosis and cell cycle arrest, as well as alteration of PC cell metabolome [17,18]. In addition, miR-1291 sensitizes PC cells to chemotherapy via direct targeting of multidrug resistance-associated protein 1 (MRP1) overexpressed in the cells [19].…”

MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma

“…Foxa2 is a member of the fork head transcription factor family which is widely involved in the regulation of cell proliferation and differentiation26, 27. Prior studies have showed that Foxa2 may be abnormally expressed in a number of cancers, which sequently lead to the development of tumors24, 28, 29.…”

“…Prior studies have showed that Foxa2 may be abnormally expressed in a number of cancers, which sequently lead to the development of tumors24, 28, 29. A number of miRNAs have been shown to be able to regulate Foxa2 expression such as miR-1291, miR-29 and miR-124a27, 30, 31. But the potential relationship of miR-200a targeting Foxa2 in human hepatocellular carcinoma have not been studied before.…”