Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.Implications: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets.

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

“…This suggests that miR-223-5p exhibits an anti-proliferative activity in the vulva, and this is in line with other studies in the literature in other cancer cell lines. Overexpression of miR-223 was capable to block myeloid cell proliferation through E2F1 inhibition [27] and miR-223 was described as a suppressor of cell proliferation in malignant pleural mesothelioma cells through STMN1 targeting [28]. Inhibition of cell proliferation through IGF-1R targeting was also demonstrated [29, 30].…”

Analysis of early mesothelial cell responses to Staphylococcus epidermidis isolated from patients with peritoneal dialysis-associated peritonitis

“…No. SFBS-F) and 0.4 μg/mL hydrocortisone (Sigma-Aldrich) [16]. Met-5A mesothelial cells (ATCC ® CRL-9444) were cultured in the same formulation of DMEM as the primary mesothelial cells, but without hydrocortisone and using 10% FBS [17].…”

A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ

“…It has been shown to be over-expressed in MM cell lines and tumour samples (45) and it is over expression is consistently associated with increased metastasis and malignant growth (46). Over-expression of miR-223 and siRNA knock-down in MM cell lines reduces stathmin expression, resulting in inhibition of motility and tubulin acetylation via a JNK signalling pathway-dependant mechanism (47).…”