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Review
. 2021 May 7;10(5):1132.
doi: 10.3390/cells10051132.

Xmrks the Spot: Fish Models for Investigating Epidermal Growth Factor Receptor Signaling in Cancer Research

Jerry D Monroe  1 , Faiza Basheer  2 , Yann Gibert  1
Affiliations
Review

Xmrks the Spot: Fish Models for Investigating Epidermal Growth Factor Receptor Signaling in Cancer Research

Jerry D Monroe et al. Cells. .

Abstract

Studies conducted in several fish species, e.g., Xiphophorus hellerii (green swordtail) and Xiphophorus maculatus (southern platyfish) crosses, Oryzias latipes (medaka), and Danio rerio (zebrafish), have identified an oncogenic role for the receptor tyrosine kinase, Xmrk, a gene product closely related to the human epidermal growth factor receptor (EGFR), which is associated with a wide variety of pathological conditions, including cancer. Comparative analyses of Xmrk and EGFR signal transduction in melanoma have shown that both utilize STAT5 signaling to regulate apoptosis and cell proliferation, PI3K to modulate apoptosis, FAK to control migration, and the Ras/Raf/MEK/MAPK pathway to regulate cell survival, proliferation, and differentiation. Further, Xmrk and EGFR may also modulate similar chemokine, extracellular matrix, oxidative stress, and microRNA signaling pathways in melanoma. In hepatocellular carcinoma (HCC), Xmrk and EGFR signaling utilize STAT5 to regulate cell proliferation, and Xmrk may signal through PI3K and FasR to modulate apoptosis. At the same time, both activate the Ras/Raf/MEK/MAPK pathway to regulate cell proliferation and E-cadherin signaling. Xmrk models of melanoma have shown that inhibitors of PI3K and MEK have an anti-cancer effect, and in HCC, that the steroidal drug, adrenosterone, can prevent metastasis and recover E-cadherin expression, suggesting that fish Xmrk models can exploit similarities with EGFR signal transduction to identify and study new chemotherapeutic drugs.

Keywords: Xiphophorus; Xmrk; cancer; drug discovery; epidermal growth factor receptor; melanoma; signal transduction; zebrafish.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Xmrk signaling in the Xiphophorus melanoma model. Xiphophorus melanoma receptor kinase (Xmrk) is a receptor tyrosine kinase that recruits and activates several kinases, transcription factors and adaptor proteins integrated into signaling networks to regulate pigment cell cancer transformation. Activation of the kinase, phosphoinositide 3-kinase (PI3K), prevents apoptosis in malignant cells, as does activation of the transcription factor, signal transducer and activator of transcription 5 (STAT5), via B-cell lymphoma (Bcl-x) signaling, and STAT5 also promotes proliferation. The Src kinase protein, Fyn, acts as a docking protein and, through focal adhesion kinase (FAK), can induce pigment cell migration. Further, Fyn inhibits MAPK phosphatase 1 (MKP-1), a repressor of MAPK, causing the promotion of MAPK’s function to increase melanoma cell proliferation. Xmrk can also signal via the adaptor proteins, GRB2 and Sos, to activate the Ras/Raf/MEK/MAPK pathway, thereby enhancing proliferation. Additionally, MAPK signaling causes degradation of the transcription factor, microphthalmia transcription factor (MITF), leading to reduced transcription of tyrosinase, which decreases melanin synthesis and inhibits pigment cell differentiation. Another function of activated MAPK is to induce the synthesis of osteopontin (OPN), which is secreted, binds to integrins on the cell membrane surface, and promotes pigment cell survival. Several miRNAs that are regulated in fish Xmrk models also have functions in human melanoma. The miRNAs miR-18a, -182, and -214, can act to promote migration in human melanoma, while miR-182 and -214 can also stimulate cell survival. MiR-17, 125b, and -126 act to inhibit melanoma cell migration, with -125b’s action inhibited by FAK. MiR-17, along with miR-18a, also function to increase melanoma proliferation.
Figure 2
Figure 2
Xmrk signaling in the zebrafish hepatocellular carcinoma model. In transgenic zebrafish models of HCC, Xmrk signals through kinases and transcription factors that modulate liver cancer progression. PI3K activation may modulate apoptosis through the mechanistic target of rapamycin (mTOR), although mTOR expression may be decreased in HCC, making its effect on apoptosis uncertain. STAT5 signaling can promote proliferation, as does MAPK via activation of extracellular signal-regulated kinases (ERK). MAPK also has a dual role in signaling through the transcription factors, Snail and Slug, to inhibit E-cadherin activity. The formation of focal adhesions is increased through a pathway that is currently uncharacterized. Xmrk is also associated with increased expression of the tumor suppressor, p53, and the Fas receptor (FasR), which regulates apoptosis during HCC, but the details of their associated signaling mechanisms are not currently understood.
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