Increase of miR-199a-5p by protoporphyrin IX, a photocatalyzer, directly inhibits E2F3, sensitizing mesenchymal tumor cells to anti-cancer agents

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Protoporphyrin IX (PPIX) has been used for photodynamic therapy. Mesenchymal cancer cells adapt to tumor microenvironments for growth and metastasis possibly in association with miRNA dysregulation. In view of the effect of PPIX on cancer-related genes, and its potential to inhibit tumor growth and migration/invasion, this study investigated whether PPIX enables mesenchymal liver tumor to restore dysregulated miRNAs, and if so, whether it sensitizes the cancer cells to chemotherapy. In addition, we explored new target(s) of the miRNA(s) that contribute to the anti-cancer effects. Of the ten miRNAs predicted by the 3′-UTR of HIF-1α mRNA, PPIX treatment increased miR-199a-5p, leading to the inhibition of E2F3 expression which is upregulated in mesenchymal liver tumor. miR-199a-5p levels were downregulated in HCC with E2F3 overexpression. An approach modulating epithelial-mesenchymal transition provided the expected changes in miR-199a-5p and E2F3 in vivo. PPIX prevented tumor cell growth and migration/invasion, and had a synergistic anti-cancer effect when combined with chemotherapeutics. In a xenograft model, PPIX treatment decreased overall growth and average tumor volume, which paralleled E2F3 inhibition. Overall, PPIX inhibited growth advantage and migratory ability of cancer cells and sensitized mesenchymal liver tumor cells to chemotherapeutics.

MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells

“…Recently, miR-199a-5p has been reported to exhibit inhibitory effects on autophagy (27). For instance, Lee et al observed that protoporphyrin IX, a photocatalyzer, could increase the expression of miR-199a-5p, which further inhibited E2F transcription factor 3 and sensitized mesenchymal tumor cells to chemotherapy drugs (28). In the present study, it was observed that miR-199a-5p inhibited DDP-induced autophagy.…”

MiR‐199a‐5p suppresses tumorigenesis by targeting clathrin heavy chain in hepatocellular carcinoma

“…It is well known that miRNAs function via regulating their target protein by binding to the 3’ untranslated regions (UTRs) of target messenger RNAs (mRNAs), resulting in mRNA degradation or the blockade of mRNA translation . Previously, miR‐199a‐5p was reported to functions as a tumor suppressor by targeting connective tissue growth factor (CTGF), integrin β1, hypoxia‐inducible factor 1 alpha (HIF‐1α), E‐cadherin, hexokinase 2, frizzled class receptor 6 (FZD6), E2F transcription factor 3 (E2F3), Wnt family member 2 (WNT2) and cyclin‐dependent kinase inhibitor 1C (P57, CDKN1C) …”

“…In present study, we showed that miR-199a-5p, frequently down- 19,20 Previously, miR-199a-5p was reported to functions as a tumor suppressor by targeting connective tissue growth factor (CTGF), integrin β1, hypoxia-inducible factor 1 alpha (HIF-1α), E-cadherin, hexokinase 2, frizzled class receptor 6 (FZD6), E2F transcription factor 3 (E2F3), Wnt family member 2 (WNT2) and cyclin-dependent kinase inhibitor 1C (P57, CDKN1C). [21][22][23][24][25][26][27][28][29] Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. 30 In the past decades, most of studies were focused on clathrin mediated endocytosis.…”

MiRNAs and E2F3: a complex network of reciprocal regulations in human cancers

“…In HCC, miR-199a-5p levels were down-regulated accompanied by E2F3 overexpression. After PPIX treatment, miR-199a-5p was modulated to increase and led to the inhibition of E2F3 expression [ 53 ]. In murine models of colon cancer, miR-143 and miR-145 played tumor suppressive functions by targeting Cdk6, CCND2 and E2F3 [ 54 ].…”