GPR39 Overexpression in OSCC Promotes YAP-Sustained Malignant Progression

Abstract

<jats:p> The clinical outcome of oral squamous cell carcinoma (OSCC) has not improved in recent years, mainly due to the limited effective targeted therapy that has been applied. Recently, a transcriptional coactivator, YAP, has been shown to have a key regulatory role in malignant progression in multiple cancers, including OSCC. But pharmacologically targeting YAP or the Hippo pathway, which is the main signaling pathway regulating YAP, has been proven to be challenging. Therefore, uncovering YAP upstream regulators in cancer would identify novel therapeutic targets for treatment of YAP-sustained cancers. Here, we showed that YAP was overactivated in OSCC and that high YAP activity in patients with OSCC was associated with malignant progression and poor survival. We uncovered that GPR39 (a G protein–coupled receptor) was overexpressed in OSCC, that the expression level of GPR39 was correlated with the activity level of YAP, and that the high GPR39 expression was associated with malignant progression and poor survival in patients with OSCC. Moreover, we found that GPR39 regulated YAP through a Gαq/11-RhoA–dependent signaling pathway. Importantly, inhibition of GPR39 resulted in YAP-sustained OSCC growth inhibition. Our findings suggest that GPR39 is a potential therapeutic target for OSCC treatment with itself as a biomarker. </jats:p>

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic–ischemic injury in rats

“…GPR39 plays an important role in wound healing, depression, inflammatory bowel diseases, alcohol use disorder, insulin secretion and several cancers [ 23 , 46 , 48 – 52 ]. However, the neuroprotective function of GPR39 has been partially confirmed.…”

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

“…GPR39 plays an important role in wound healing, depression, in ammatory bowel diseases, alcohol use disorder, insulin secretion and several cancers [23,46,[48][49][50][51][52]. However, the neuroprotective function of GPR39 has been partially con rmed.…”

“…Activation of GPR39 and related subsequent signaling cascade has been identi ed in several cells and shown to regulate a vast array of physiological functions, such as proliferation, differentiation, ion transport and tight junction formation [16]. Moreover, activation of GPR39 has been demonstrated to promote wound healing, ameliorate symptoms of in ammatory bowel diseases, dampen epileptic seizure activity, reduce anxietylike behaviors and regulate insulin secretion and malignant progression of several cancers [17][18][19][20][21][22][23][24]. Recently, accumulating in vitro evidence demonstrated that GPR39 exhibits anti-in ammatory activity by reducing the expression of pro-in ammatory cytokines(IL-1β IL-6), enhancing anti-in ammatory cytokines production (IL-10), ameliorating oxidative stress and mitochondrial dysfunction [25][26][27].…”

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

“…GPR39 has been reported to regulate gastrointestinal motility and secretion, food intake, insulin secretion, tissue repair, apoptosis and synaptic transmission [20], mediating intracellular signaling pathways [21]. Coincidentally, the dysregulation and involvement of GPR39 in the development and progression of cancer have been also observed [22][23][24][25][26]. Here we strove to find additional modes of HBV proliferation through the properties of GPR39, also investigating novel features of the receptor through HBV replication machinery.…”