ACTG2 is often aberrantly expressed in multiple cancers [
15,
17,
18], and low levels have been associated with worse disease-specific survival [
16]. Previously, low mRNA expression levels of
ACTG2 were demonstrated in metastases relatively to primary SI-NETs [
10]. To investigate a possible role and function of
ACTG2 in SI-NET tumorigenesis this finding was first confirmed by immunohistochemistry, demonstrating absence of protein expression in the majority of investigated SI-NETs. Interestingly, eight primary tumors and two lymph node metastases displayed positive staining for ACTG2 in tumor cells, albeit at variable level and appearance. We could not detect ACTG2 expression in the enterochromaffin cells of the normal intestinal mucosa, suggesting that expression of
ACTG2 can be induced at some point during tumor progression representing a dedifferentiated phenotype, rather than being normally expressed in this cell type. Induction of
ACTG2 at some point during primary tumor growth may have beneficial effects as
ACTG2 showed growth inhibitory effects, at least in vitro. Expression of
ACTG2 was detected in stromal cells and whether ACTG2 can display growth effects here remains to be investigated.
This study demonstrated that expression of
ACTG2 can be induced by DZNep treatment or miR-145 transfection of the human SI-NET cell line CNDT2.5. Treatment with DZNep also induced expression of miR-145, indicating a possibility that induction of
ACTG2 by DZNep may be due to the effects on miR-145 expression. DZNep is a potential drug in cancer treatment [
29]. DZNep can inhibit the histone methyltransferase EZH2, which is the catalytic subunit of polycomb repressive complex 2 and is responsible for methylation of lysine 27 on histone 3, a repressive mark [
30]. A role of EZH2 was however excluded here since EPZ-6438, a newly developed specific drug inhibiting EZH2 enzymatic activity [
28], was not able to induce
ACTG2 expression. MiR-145 is often deregulated in cancer cells [
31,
32] and is known to induce
ACTG2 expression in breast cancer [
19]. Here, it is demonstrated that this occurs also in SI-NET cells; overexpression of miR-145 increased expression of
ACTG2 in vitro
. There was a decrease of miR-145 expression in metastasis compared to primary tumors, as observed for
ACTG2 [
10]. Low levels of
ACTG2 are correlated to chemotherapy resistance [
12,
14] and inducing this gene in SI-NETs would, not only have a growth inhibitory effect, but also potentially make the tumors more sensitive to treatment. SI-NETs are difficult to cure due to their resistance to chemotherapy and radiation, and new treatment strategies are warranted. MicroRNAs are involved in gene regulation and cancer development, and thus, have a potential role as therapeutic targets. miR-145 has been suggested to be a candidate for RNA medicine in colon tumors with a reduced expression [
33]. miR-145 have multiple gene targets, and seems to be able to act as both a tumor suppressor and an oncogene depending on tumor type. Ruebel et al. [
34] detected a difference in expression levels of miR-145 between primary SI-NETs and metastases, and here we confirmed a decrease in expression by tumor progression. These results suggest that miR-145 may be a tumor suppressor and may be important for the ability to metastasize. Inducing or introducing miR-145 may be a potential new therapeutic strategy in SI-NETs.