Abstract
BackgroundActivin-A may exert pro- or anti-tumorigenic activities depending on cellular context. However, little is known about its role, or the other mature activin proteins, in colorectal carcinoma (CRC). This study measured the expression of activin βA- & βB-subunits, activin type IIA & IIB receptors, smads 2/3/4/6/7 and follistatin in CRC induced by azoxymethane (AOM) in rats. The results were compared with controls and disseminated according to the characteristics of histopathological lesions.MethodsEighty male Wistar rats were allocated into 20 controls and the remaining were equally divided between short ‘S-AOM’ (15 weeks) and long ‘L-AOM’ (35 weeks) groups following injecting AOM for 2 weeks. Subsequent to gross and histopathological examinations and digital image analysis, the expression of all molecules was measured by immunohistochemistry and quantitative RT-PCR. Activin-A, activin-B, activin-AB and follistatin were measured by ELISA in serum and colon tissue homogenates.ResultsColonic pre-neoplastic and cancerous lesions were identified in both AOM groups and their numbers and sizes were significantly (P < 0.05) greater in the L-AOM group. All the molecules were expressed in normal colonic epithelial cells. There was a significantly (P < 0.05) greater expression of βA-subunit, IIB receptor and follistatin in both pre-neoplastic and cancerous tissues. Oppositely, a significant (P < 0.05) decrease in the remaining molecules was detected in both AOM groups. Metastatic lesions were only observed within the L-AOM group and were associated with the most significant alterations of all molecules. Significantly higher concentrations of activin-A and follistatin and lower activin-AB were also detected in both groups of AOM. Tissue and serum concentrations of activin-A and follistatin correlated positively, while tissue activin-AB inversely, and significantly with the numbers and sizes of colonic lesions.ConclusionsNormal rat colon epithelial cells are capable of synthesising, controlling as well as responding to activins in a paracrine/autocrine manner. Colonic activin systems are pathologically altered during tumorigenesis and appear to be time and lesion-dependent. Activins could also be potential sensitive markers and/or molecular targets for the diagnosis and/or treatment of CRC. Further studies are required to illustrate the clinical value of activins and their related proteins in colon cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2914-9) contains supplementary material, which is available to authorized users.
Highlights
Activin-A may exert pro- or anti-tumorigenic activities depending on cellular context
Activins belong to the Transforming growth factor (TGF-β) family and the mature activins consist of hetero- or homodimers of 2 βsubunits resulting in three distinct proteins named activin-A, activin-B and activinAB [10]
The canonical pathway for activins, following the activation of their type II receptors (ACTRIIA & Activin type IIB receptor (ACTRIIB)), shares the same intracellular mediators with transforming growth factor (TGF)-β and both are dependent on smad2, 3 and 4 [11]
Summary
Activin-A may exert pro- or anti-tumorigenic activities depending on cellular context. Several molecular pathways are pathologically skewed during colon tumorigenesis [8] Among these pathways, the members of transforming growth factor (TGF)-β family have recently been suggested as potential stagedependent targets for the treatment of CRC and/or prevention of resistance associated with chemotherapy [9]. The canonical pathway for activins, following the activation of their type II receptors (ACTRIIA & ACTRIIB), shares the same intracellular mediators with TGF-β and both are dependent on smad and 4 [11]. Extracellular neutralising molecules include the well-established activin binding protein, follistatin, which binds the three mature isoforms of activin with similar affinity and prevents their interactions with type II receptors [12]. Physiological intracellular inhibitors of activins and TGF-β signals are known as inhibitory smads (smad6 & 7) and both inhibit the phosphorylation of receptor smads (smad2 & 3), prevent their interactions with smad as well as induce the degradation of activated activin and TGF-β type I receptors [11]
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