Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis

Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis

With the recent advent of whole genome and transcriptome sequencing technologies, long non-coding RNAs have been brought into the spotlight in molecular biology. H19 was one of the first reported long non-coding RNAs; its expression is high in embryonic organs and absent or greatly reduced in most adult tissues. Accumulating evidence suggests that H19 plays crucial roles in embryogenesis. However, its levels are increased in different cancers, including breast, hepato-gastrointestinal, urological, respiratory, and brain tumors. Although there have been several controversial reports as to whether H19 is oncogenic or tumor-suppressive, most studies have indicated that H19 is associated with growth, migration, invasion, and/or metastasis in many cancers; however, its reported functional mechanisms vary among cancer types. Furthermore, serum H19 levels in patients with certain cancers have been suggested to be useful for diagnosis and prognosis. Thus, H19 long non-coding RNA might be a candidate for development of promising therapeutic and diagnostic modalities for several cancers. The purpose of this review is to provide an inclusive report on the functional role of H19 in different cancers.

Epithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1 expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs but weak in poorly differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly differentiated cancers. Increased ESRP1 expression was associated with longer survival in comparison with low ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to upregulate ESRP1 may exert a beneficial therapeutic effect in PDAC.