A microRNA‐7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib‐resistant cells in human hepatocellular carcinoma

Abstract

Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient, and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TYRO3-AXL-MER family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC; however, its role in SR is unknown. In this study, we generated two functionally distinct sorafenib-resistant human Huh-7 HCC cell lines in order to identify new mechanisms to abrogate acquired SR as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA (miR), miR-7-5p (miR-7), in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumor suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration, and invasion of Huh-7 cells through the phosphoinositide 3-kinase/protein kinase B pathway and is markedly elevated with acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib-resistant Huh-7 cells, inhibiting TYRO3/growth arrest specific 6-mediated cancer cell migration and invasion. Conclusion: We identified a mechanism for acquiring SR in HCC that is through the aberrant expression of the TYRO3/phosphoinositide 3-kinase/protein kinase B signal transduction pathway, and that can be overcome by miR-7 overexpression. Taken together, these data suggest a potential role for miR-7 as an RNA-based therapeutic to treat refractory and drug-resistant HCC. (HEPATOLOGY 2018;67:216-231) L iver cancer ranks sixth among all malignancies in the world and is the second leading cause of cancer-related mortality. (1) The rising incidence of hepatocellular carcinoma (HCC), the most common primary malignant neoplasm of the liver, has been linked to hepatitis B or C infection and increasing worldwide obesity associated with fatty liver disease. (2) In 2017, it is estimated that 40,710 patients will be diagnosed with HCC in the United States, and more than 70% of them will eventually die from this

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

“…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.…”

“…melanoma cells [37]. Inhibition studies have also revealed a role for Tyro3 in metastasis, reflected in decreased cancer cell migration and invasion [25]. Furthermore, Tyro3 has also been implicated as a mediator of resistance to anti-cancer agents [6].…”

MicroRNA‑191‑5p exerts a tumor suppressive role in renal cell carcinoma

“…Subsequently, numerous studies demonstrated that miRNAs serve important roles in various carcinomas (22)(23)(24)(25)(26). In addition, Polioudakis et al (27) reported that miRNAs are located at 50% of all fragile regions or sites presenting copy number alterations in cancer.…”

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

“…Increasing evidence indicates that miRNAs are aberrantly expressed in various types of cancer, and the dysfunction of miRNAs has a crucial role in tumor initiation, invasion, and metastasis (5,6). Recent studies have demonstrated that miRNAs are correlated with the proliferation, angiogenesis, drug resistance, and prognosis of HCC (7)(8)(9)(10).…”