Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression

Abstract

Abstract. While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations. Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment.

Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis

“…While numerous studies have described signalling pathways downstream of Axl and MerTK and the changes following stimulation with TAM ligands [12,13], relatively few studies have directly assessed signalling pathways downstream of Tyro3, particularly in cancers. Tyro3 was early on found to be autophosphorylated upon overexpression in a ligand-independent manner, and an association with Src kinase was detected [4,26]. In bone, Gas6 was shown to stimulate mouse osteoclast function via Tyro3, involving activation of Erk [22] and Erk signalling mediated Tyro3 regulation of proliferation in breast cancer [27].…”

“…Tyro3 knockdown studies in tumour xenograft models have shown a role for Tyro3 in tumour progression, as well as the association of Tyro3 expression with poor prognosis in, amongst others, colorectal, hepatocellular, breast, and bladder cancers [28,36]. Tyro3 has also been linked to Akt signaling and cell survival regulation in e.g., hepatocellular carcinoma [25,26]. Tyro3 shRNA knockdown promoted apoptosis and decreased anchorage-independent growth in e.g.…”

A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

“…Although foretinib and sorafenib have many common targets, an extended analysis of those unique to each in future trials may shed light on activity differences and inform patient selection. Recent studies reveal certain targets unique to foretinib that deserve further interrogation: TYRO3 was shown to be overexpressed in HCC tumors and linked to HCC cell growth in vitro [30], AXL protein abundance was positively correlated with lymph node metastasis and HCC clinical stage [31], and AXL pathway activation promoted autocrine transforming growth factor-β signaling [32] and invasiveness through activation of SNAI2 [33] in HCC cell lines, as well as HCC xenograft growth in mice [31]. …”

Tyro3 carboxyl terminal region confers stability and contains the autophosphorylation sites

“…Abnormal expression of Axl and MerTK has been widely reported in many cancer cells [7];[8];[9];[10];[11]. Compared to Axl and MerTK, Tyro3 is the least studied although recently accumulating evidence revealed that the expression of Tyro3 is elevated in several cancer cells such as ovarian cancer, hepatocellular carcinoma, colon cancer and melanoma [12];[13];[14];[15];[16]. For example, Lee reported that overexpression of Tyro3 leads to a resistance in ovarian cancer cells to chemotherapeutic drug taxol [12].…”