Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer

Abstract

We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M‐hSef) or empty vector controls (PC3M‐EV) were injected subcutaneously into the lateral thoracic walls of NOD‐SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M‐EV xenografts had definitive lung micro‐metastasis whilst only 1/6 PC3M‐hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over‐expression and silencing reciprocally altered E‐Cadherin expression (p = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E‐Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK‐MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context.

ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism

“…However, the optimization of IL17RD detection antibodies for pathological purposes will be critical to further assess its role in predicting patient response to clinical MEK inhibitors. Because IL17RD is involved during development (43, 56), is a negative regulator of EMT (57, 58), and causes metastasis to become predominantly dependent upon MAPK signaling, the broader role of IL17RD in counter regulation and restructuring of global cell signaling patterns warrants future studies. Lastly, in addition to ZEB1 regulating IL17RD-mediated MAPK signaling, validation of our RPPA data revealed a continuous decrease in p90RSK with ZEB1 expression, which did not follow the same pattern as upstream MAPK signaling molecules.…”

Cross-Talk between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins

“…Sef can also induce apoptosis and affect FGF-induced differentiation in various cell types [255]. Notably, the FGFRs-Sef interplay was implicated in prostate cancer [256,257].…”

Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling

“…Expression of IL17RD has been shown to be inversely proportional to the degree of aggressiveness of tumors originating from the epithelia of organs such as breast, prostate, thyroid, ovaries and intestine [48][49][50]. In this context, ectopic expression of IL17RD was shown to regulate the biological response to FGF, EGF as well as the WNT signaling pathways by not only regulating the proliferation, migration and invasiveness of carcinoma cells, but also the expression of EMT markers to suppress the metastatic transformation of the tumors [35,36,44,48,49,51,52]. Additionally, IL17RD was shown to promote the sensitivity of resistant metastatic lung cancer cells to therapeutic MEK inhibitors [35].…”