MicroRNA-221 and MicroRNA-222 in Common Human Cancers

Expression, Function, and Triggering of Tumor Progression as a Key Modulator

Sima Amini, MSc; Atefe Abak, MSc; Ebrahim Sakhinia, PhD; Alireza Abhari, PhD

Disclosures

Lab Med. 2019;50(4):333-347. 

In This Article

Regulation of MiR-221/-222 Expression

Molecular mechanisms that regulate miR-221/-222 expression have been investigated in certain studies. Stinson et al[12] reported that FOS-like 1 activator protein 1 transcription factor subunit (FOSL1) positively regulates transcription of miR-221/-222. They demonstrated that the epidermal growth factor receptor (EGFR)–RAS-RAF–mitogen-activated protein kinase kinase (MEK)–ERK2-FOSL1 signaling axis regulates miR-221/-222 expression and subsequently promotes EMT in BLBC. To form activator protein 1 (AP-1) complexes, heterodimerization occurred between FOSL1 (as a member of the FOS family) and a member of the Jun family. Transfection of MEK inhibitor (MEKi) into BLBC cell lines led to a decrease in the abundance of miR-221/-222, showing that miR-221/-222 release is organized by the RAS-RAF-MEK axis. MEKi treatment diminished the expression level of FOSL1.

The abundance of E-cadherin increased and vimentin decreased in these cell lines by MEKi treatment, indicating that they become more epithelial. Treatment of CAL85-1 cells with EGFR siRNA reduced extracellular signal-regulated kinase (ERK)1/-2 phosphorylation and expression of miR-221/-222. EGFR inhibitor did not alter the abundance of miR-221/-222 in MDA-MB-231 cells with active RAS mutations. This observation demonstrated that EGFR controls the expression of miR-221/-222 through the RAS-RAF-MEK cascade.[12] Figure 3A indicates an axis that regulates miR-221/-222 in breast cancer.

Garofalo et al[31] reported another mechanism for miR-221/-222 activation in NSCLC and malignant hepatoma. The study results revealed that activation of miR-221/-222 is partially regulated by the c-MET oncogene and c-Jun transcription factors. The results indicated that c-Jun contributes to miR-221/-222 regulation, unlike c-Fos. They also found an AP-1 binding site in 130bp upstream of miR-221/-222. Activation of the MET oncogene leads to upregulation of miR-221/-222 through the c-Jun N-terminal kinase (JNK) cascade. MiR-221/-222 overexpression leads to downregulation of PTEN and TIMP3, which subsequently resulted in migration, invasion, and resistance to apoptosis in NSCLC and HCC cells. PTEN controls the PI3K/AKT pathway, which has roles in MDR and invasion. TIMP3 induces caspase 8 and caspase 9, which are important stimulants of apoptosis.

Garofalo et al suggested that the MET, JNK, AP-1 axis regulates the expression of miR-221/-222 in these malignant neoplasms.[31] The results of another study by Felicetti et al[54] illustrated that negative control of miR-221/-222 by promyelocytic leukemia zinc finger (PLZF) occurred through direct attachment to the regulatory site. Thus, knockdown of PLZF leads to upregulation of miR-221/-222. Also, the results of research by Acunzo et al[72] showed that miR-130a is a negative regulator of miR-221/-222 in NSCLC. In 2 other studies,[78,79] it was reported that high mobility group box 1 (HMGB1) and receptor for advanced glycosylation end product (RAGE) interact with each other to regulate the expression of miR-221/-222, which subsequently leads to a decrease in PTEN. HMGB1 repressed PTEN through increasing the level of miR-221/-222. The coauthors discovered that the HMGB1/RAGE–miRNA221/-222–PTEN axis controls proliferation in neuroblastoma and thyroid carcinoma.

The results of another research work[80] suggested that niche cells (such as bone-marrow stromal cells [BMSCs] and human osteoblasts) control the expression of miR-221 and miR-222 in patients with acute lymphoblastic leukemia (ALL). Due to this event, an increase in p27 levels was observed, which subsequently resulted in cell-cycle arrest and inhibition of proliferation. Another consequence is the loss of sensitivity to chemotherapy drugs.

We were surprised to learn that miRNA-221/-222 could adjust other miRNAs. A recent study report[81] declared that miR-221/-222 could reduce the overall expression levels of miRNAs by downmodulation of Dicer-1. MiR-221/-222 could inhibit Dicer-1 by binding to its 3′ untranslated region in TNBCs. Dicer is a ribonuclease III enzyme that is involved in the biogenesis of miRNAs. So, miRNAs have a complex regulatory network, and further studies should be performed to discover their complicated pathways.

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