Abstract
The STC2 protein involves in carcinogenesis and progression of many cancers. It remains unclear how STC2 regulates the epithelial-mesenchymal transition (EMT) process and colorectal cancer (CRC) development. Here we systematically investigated STC2-activated early occurrence of EMT and CRC cell migration in vitro, clinical associations of STC2 with CRC development and patient survival. The secretion and expression level of STC2 were both greatly increased in EMT cells and CRC cells compared with the normal epithelial NCM460 cells. And the conditioned media from EMT cells stimulated epithelia and colon cancer cells to obtain EMT characteristics. STC2 overexpression promoted CRC cell growth and cell migration in vitro, and STC2 enhanced tumor growth in a mouse CRC-xenograft model. Corresponding to EMT marker expression changes, several critical signaling pathway molecules including pERK, pAKT, PI3K and Ras were remarkably increased either in NCM460 cells transfected with STC2 plasmids or in cells induced with exogenous STC2 protein. However blocking AKT-ERK signaling pathways attenuated STC2-activated EMT process. Furthermore the elevated STC2 expressions were also confirmed in 77 clinical tumor tissues and sera from CRC patients, and the increased STC2 in tumor tissues and sera correlated with tumor pathologic stage and poor survival for CRC patients. In conclusion, STC2 promotes CRC tumorigenesis and EMT progression through activating ERK/MEK and PI3K/AKT signaling pathways. STC2 protein is also a potential tumor biomarker for CRC diagnosis and prognosis.
Highlights
The stanniocalcin (STC) family consists of stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2), which are glycoproteins as hormones to regulate calcium and phosphate secretion [1]
The secretion and expression level of STC2 were both greatly increased in epithelial-mesenchymal transition (EMT) cells and colorectal cancer (CRC) cells compared with the normal epithelial NCM460 cells
In order to obtain colon cells with EMT features, named as EMT cells, human colon mucosal epithelial NCM460 cells were induced into EMT cells by continuously treated with phorbol-12-myristate-13acetate (PMA), which had been used as an EMT inducer for human prostate cancer cells [17]
Summary
The stanniocalcin (STC) family consists of stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2), which are glycoproteins as hormones to regulate calcium and phosphate secretion [1]. STC was previously reported to be present in the corpuscle of stannius, an endocrine gland of bony fish associated with Ca2+ homeostasis [2]. STC1 and STC2 have been found to widely express in various human tissues [3]. Except as a calcium and phosphate regulator, STC2 exhibits potent growth-suppressive properties and participates in bone development [4]. STC2 up-regulation can be caused by the unfolded-protein response in eukaryotic cells through activating transcription factor 4 after activation of the endoplasmic reticulum kinase [5, 6]. Its roles in pancreatic cell injury were further discovered [7]
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