Short-form Ron is a novel determinant of ovarian cancer initiation and progression

Abstract

Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment.

PD-L1 Expression in Glioblastoma, the Clinical and Prognostic Significance: A Systematic Literature Review and Meta-Analysis

“…Studies have reported that glioblastomas which are hotspot mutation in IDH1 (an isoform of IDH ) generally have a significantly better prognosis compared with IDH1 -wildtype glioblastomas ( 43 – 45 ). Moreover, the expression of PD-L1 in diffuse gliomas might be directly influenced by IDH1 mutational status ( 33 , 46 , 47 ). Therefore, the relation between PD-L1 expression and IDH1 status was further investigated in the stratified analysis.…”

Targeting PDK1 for Chemosensitization of Cancer Cells

“…These findings strengthen the notion of the oncogenic capacity of PDK1 in ovarian cancer [ 32 ]. Very recently, Moxley et al demonstrated that PDK1 is implicated in ovarian cancer via an alternative splicing product of the Ron receptor tyrosine kinase, named short-form Ron (sfRon) [ 33 ]. This protein is absent from normal ovarian tissue but is strongly expressed in malignant ovarian tumours, especially in one of the most lethal types, the high-grade serous one.…”

“…This protein is absent from normal ovarian tissue but is strongly expressed in malignant ovarian tumours, especially in one of the most lethal types, the high-grade serous one. Overexpression of sfRon in OVCAR3 cells resulted in a more aggressive phenotype both in vitro and in vivo, induced epithelial-to-mesenchymal transition (EMT) reflected by vimentin and N-cadherin upregulation and E-cadherin reduction, and instigated the PDK1 signaling pathway, which was depicted by increase of pSer241-PDK1 and pThr308-/pSer473 AKT [ 33 ]. In agreement to the group’s previous studies, this model revealed that sfRon was dependent on PI3K signaling to induce EMT, one of the most crucial steps of the pathway being plasma membrane recruitment of PDK1, and this PI3K signaling effects were AKT/mTOR-independent [ 34 ].…”

“…Notably, PDK1 has previously been held accountable for EMT initiation in gallbladder cancer [ 35 ]. The fact that OVCAR3-sfRon cells had a very firm PDK1 expression compared to the absence of the protein’s expression in control OVCAR3 cells, reflects the importance of PDK1 in driving aggressiveness in ways that are not correlated to AKT, and that focus should be given on testing inhibitors of PDK1 alone or in combination with Ron inhibitors, especially in this type of ovarian cancer [ 33 ].…”

TGFβ Controls Ovarian Cancer Cell Proliferation

“…It has also been demonstrated that, in the case of clear cell carcinoma, concomitant mutations of ARID1A and PIK3CA are necessary to initiate tumor formation [ 19 ]. Other signaling pathways implicated include that for the receptor tyrosine kinases c-Met and Ron, which are thought to play a role in ovarian cancer initiation and progression [ 20 ]. Thus, it is important to identify the main signaling pathways in normal ovarian cells, and to determine how they are altered to give rise to ovarian cancer.…”