Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and become migratory mesenchymal cells. Several transcription factors, including the Snail/Slug family, Twist, δEF1/ZEB1, SIP1/ZEB2 and E12/E47 respond to microenvironmental stimuli and function as molecular switches for the EMT program. Snail is a zinc-finger transcriptional repressor controlling EMT during embryogenesis and tumor progression. Through its N-terminal SNAG domain, Snail interacts with several corepressors and epigenetic remodeling complexes to repress specific target genes, such as the E-cadherin gene (CDH1). An integrated and complex signaling network, including the RTKs, TGF-β, Notch, Wnt, TNF-α, and BMPs pathways, activates Snail, thereby inducing EMT. Snail expression correlates with the tumor grade, nodal metastasis of many types of tumor and predicts a poor outcome in patients with metastatic cancer. Emerging evidences indicate that Snail causes a metabolic reprogramming, bestows tumor cells with cancer stem cell-like traits, and additionally, promotes drug resistance, tumor recurrence and metastasis. Despite many new and exciting developments, several challenges remain to be addressed in order to understand more thoroughly the role of Snail in metastasis. Additional investigations are required to disclose the contribution of microenvironmental factors on tumor progression. This information will lead to a comprehensive understanding of Snail in cancer and will provide us with novel approaches for preventing and treating metastatic cancers.

GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Gprc5a– knockout mice develop spontaneous lung cancer, indicating Gprc5a is a lung tumor suppressor gene. GPRC5A expression is frequently suppressed in majority of non-small cell lung cancers (NSCLCs), however, elevated GPRC5A is still observed in a small portion of NSCLC cell lines and tumors, suggesting that the tumor suppressive function of GPRC5A is inhibited in these tumors by an unknown mechanism. In this study, we examined EGF receptor (EGFR)-mediated interaction and tyrosine phosphorylation of GPRC5A by immunoprecipitation (IP)-Westernblot. Tyrosine phosphorylation of GPRC5A by EGFR was systematically identified by site-directed mutagenesis. Cell proliferation, migration, and anchorage-independent growth of NSCLC cell lines stably transfected with wild-type GPRC5A and mutants defective in tyrosine phosphorylation were assayed. Immunohistochemical (IHC) staining analysis with specific antibodies was performed to measure the total and phosphorylated GPRC5A in both normal lung and lung tumor tissues. We found that EGFR interacted with GPRC5A and phosphorylated it in two conserved double-tyrosine motifs, Y317/Y320 and Y347/ Y350, at the C-terminal tail of GPRC5A. EGF induced phosphorylation of GPRC5A, which disrupted GPRC5A-mediated suppression on anchorage-independent growth of NSCLC cells. On contrary, GPRC5A-4 F, in which the four tyrosine residues have been replaced with phenylalanine, was resistant to EGF-induced phosphorylation and maintained tumor suppressive activities. Importantly, IHC analysis with anti-Y317/Y320-P sites showed that GPRC5A was non-phosphorylated in normal lung tissue whereas it was highly tyrosine-phosphorylated in NSCLC tissues. GPRC5A can be inactivated by receptor tyrosine kinase via tyrosine phosphorylation. Thus, targeting EGFR can restore the tumor suppressive functions of GPRC5A in lung cancer.

Background: Hepatitis B virus–related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality. This study aimed to determine the diagnostic and prognostic role of MER tyrosine kinase (MERTK) in patients with HBV-ACLF. Methods: Transcriptomics analysis evaluated MERTK expression and function during disease progression. The diagnostic and prognostic significance of MERTK for patients with HBV-ACLF were verified by enzyme-linked immunosorbent assay, area under the receiver operating characteristic curve (AUROC) analysis, and immunohistochemistry (IHC) of liver tissues. Results: MERTK mRNA was highly expressed in patients with HBV-ACLF compared to those with liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NC). Elevated MERTK mRNA predicted poor prognosis for HBV-ACLF at 28 and 90 days (AUROC = 0.814 and 0.731, respectively). Functional analysis showed MERTK was significantly associated with toll-like receptor and inflammatory signaling and several key biological processes. External validation with 285 plasma subjects confirmed the high diagnostic accuracy of plasma MERTK for HBV-ACLF (AUROC = 0.859) and potential prognostic value for 28- and 90-day mortality rates (AUROC = 0.673 and 0.644, respectively). Risk stratification analysis indicated higher mortality risk for patients with plasma MERTK level above the cutoff value. Moreover, IHC staining showed increasing MERTK expression from NC, CHB, and LC to HBV-ACLF. Conclusions: MERTK shows promise as a candidate biomarker for early diagnosis and prognosis of HBV-ACLF.