The number of patients with ATC makes up a small fraction of thyroid cancer, but the survival rate is often less than one year. Therefore, appropriate treatments are desperately needed. Mutations in BRAF are commonly seen in thyroid carcinoma [24]. Understanding the role of epigenetic changes in thyroid cancer can provide valuable opportunities to identify molecular mechanisms to provide novel therapeutic approaches. Epigenetic changes can affect miRNA expression [25]. MiRNAs can have regulatory effects on tumorigenesis, cancer cell proliferation, and other physiological processes [26]. They can act as tumor suppressors or oncogenes in different types of cancer because they can target different genes [7, 8]. Based on the findings, we examined the expression of mRNAs in the SW1736 cell line using microarrays.
In our study, increased expression of miR-217 in VPA-treated SW1736 cells showed that it could increase apoptosis of cells in anaplastic thyroid cancer. VPA increased the expression level of miR-217 by inhibiting HDAC. In a study by Zhu L and colleagues, it was found that MAPK1 is a target of miR-217. MiR-217 inhibits MAPK1 and reduces cell viability, migration, and invasion while enhancing cell apoptosis. They have introduced miR-217 as a tumor suppressor gene in cervical cancer [27]. Another study found that miR-217 expression was different in normal pancreatic cells compared with pancreatic cancer cells. And the increased expression of miR-217 inhibits cell growth and invasion of cancer cells, in contrast to the effect on E2F3 that induces apoptosis [28]. Other studies have shown that miR-217 binds to its target mRNA and acts as a tumor suppressor gene in gastric and liver cancers [29, 30].
Studies have shown that miR-138 is less expression in thyroid cancer than in normal thyroid tissue [31]. Low expression of miR-138 is associated with increased cell migration. MiR-138-5p has been shown to directly target Vim (vimentin) in cancer cells. These changes allow cancer cells to migrate [32]. In our study, expression of this miRNA increased after treatment with VPA, indicating a positive effect of VPA on our studied cell line. And introduced miR-138 as a tumor suppressor gene.
The expression level of miR-15a in PTC tissue is lower than in normal tissue. Overexpression of miR-15a prevents the proliferation and invasion of PTC cells and induces apoptosis. Overexpression of miR-15a by targeting RET and AKT inhibits tumor growth [33]. In another study, increased expression of miR-15a-5p inhibited proliferation of HepG2 or SNU-182 cancer cells in vitro [34]. In our study, expression of miR-15a-5p was also increased after the treatment of the studied cell line. In fact, VPA increased miR-15a-5p expression by inhibiting HDACs. The increased expression of miR-15a-5p prevented the proliferation of the SW1736 cell line, in fact, this miRNA activated the apoptotic mechanisms in these cells.
The results of our study showed that miR-323a-5p expression was induced by VPA on the SW1736 cell line which induced apoptosis of cells. And showed that VPA has antitumor activity. In other words, VPA by inhibiting HDAC could increase 323-miR expression. This increase in expression suppresses the tumor. One group showed that miR-323a-5p has a tumor suppressor function in neuroblastoma cells. And increased levels of miR-323a-5p decrease the proliferation of neuroblastoma cells [35]. A study by Men Y and colleagues found that miR-323a-3p expression was lower in esophageal cancer cell lines than in healthy esophageal epithelial cells and inhibits cell proliferation. Besides, miR-323a-3p prevented cell migration and invasion in some of these cell lines. These results further revealed the tumor suppressor status for miR-323a-3p [36].
In contrast, some miRNAs act as oncogenes. The expression of these miRNAs in cancer cells is higher than in healthy cells. These miRNAs induce cell proliferation and suppress apoptosis in the cell, leading the cells to become cancerous. MiR-184 has an oncogenic role in SCC squamous cell carcinoma. In a study by Wong TS and colleagues, plasma miR-184 levels were significantly higher in patients with SCC compared to normal subjects. They induced apoptosis of these cells by inhibiting miR-184 in cancer cells of the tongue [37]. Another study showed that miRNA-184 levels were higher in the EGFRm-BM group than in the control group [38]. A team of researchers showed that miR-184 enhances the biological behavior of cancer by targeting FIH-1 in the human glioma cell line A172 [38]. In microarray data analysis we found that expression of this miRNA in our SW1736 cell line was higher than in the control group. Expression of miR-184 decreased after treatment with VPA. By targeting other genes, VPA decreases miR-184 expression. By reducing this miRNA activates the mechanisms that induce apoptosis.
The cell cycle is controlled by a variety of factors. One of these factors is p27, which suppresses the cell cycle. These factors involved in the cell cycle are regulated by miRNAs. The observed miR-222 targeting p27 enhances cell proliferation. And acts as an oncogene [39, 40]. Some studies confirmed the effects of increased miR-222 expression on cancer cell metastasis [41, 42]. Inhibition of miR-222 results in PTEN rearrangement. As a result, cell proliferation and invasion are significantly suppressed and apoptosis is increased [43]. In our study, this miRNA was also increased in the studied cell lines and was identified as an oncogene in line with previous studies. Our drug was able to reduce the expression of miR-222. We have shown that VPA inhibits miR-222 by epigenetic changes and induces apoptosis in cells.
The level of miR-328-3p in ovarian cancer stem cells (CSC) is very high and may play an important role in the metastasis of these cells. Inhibition of miR-328 in rat ovarian xenografts inhibited tumor growth and prevented tumor metastasis [44]. In our study, a decrease in miR-328 was observed with Valproic acid. Our data showed that our drug reduced the expression of this miRNA and had antitumor effects.
One study found that treatment with imatinib alone was not able to grow anaplastic cells in thyroid cancer cells, but that combination therapy (imatinib and VPA) had a cytostatic effect. This effect is mediated by stunted G1 growth and acts through p21 expression and impaired AKT phosphorylation [45]. So combination therapies can be very helpful.