Pancreatic Ductal Adenocarcinoma Carcinoma Research Articles

Brucein D augments the chemosensitivity of gemcitabine in pancreatic cancer\xa0via inhibiting the Nrf2 pathway

BackgroundGemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered clinically. Nrf2, an oxidative stress responsive transcription factor, is an important contributor to chemoresistance and poor prognosis of PDAC. Brucein D (BD), a naturally occurring quassinoid, has been reported to exert anti-tumor effect in several cancers including PDAC. In this study, we aimed to investigate the efficacy of BD and the role of Nrf2 axes on the chemosensitivity of GEM and elucidate the underlying molecular mechanisms.MethodsAnalyses of clinical samples of PDAC and GEPIA database were first conducted to identify the expression of Nrf2 in PDAC. We then established cell lines with stable deletion of Nrf2 through transfecting lentivirus into PDAC cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the expression of Nrf2 in these cell lines. The effects of BD and Nrf2 axes on PDAC cell proliferation, colony-formation, tumor growth and chemosensitivity were determined both in vitro and in vivo. Orthotopic xenograft and genetically engineered KPC mouse models of PDAC were used to evaluate the anti-pancreatic cancer effects of BD and GEM.ResultsNrf2 was highly expressed in PDAC in the clinical samples and GEPIA analysis. Gain- and lost-function study demonstrated that Nrf2 affected the chemosensitivity of GEM on PDAC cells both in vitro and in vivo. We further found that BD effectively inhibited PDAC cell proliferation and enhanced the chemosensitivity of GEM. Mechanistic studies revealed that BD sensitized GEM in PDAC cells through the ubiquitin–proteasome-dependent degradation of Nrf2, and downregulating the Nrf2 pathway. Silencing of Nrf2 plus BD treatment resulted in more potent inhibitory effects of GEM. In contrast, Nrf2 activation attenuated the chemosensitivity of GEM, indicating that the action of BD was Nrf2 dependent. Finally, the efficacy of BD alone and in combination with GEM on PDAC was validated on both orthotopic xenograft and genetically engineered KPC mouse models.ConclusionsBD was able to enhance the chemosensitivity of GEM in PDAC through inhibition of the Nrf2 pathway. Our experimental findings indicate that BD, a potent Nrf2 inhibitor, holds promise for further development into a novel adjuvant therapy for PDAC.

SMAD4 Y353C promotes the progression of PDAC

BackgroundSMAD4 is frequently inactivated and associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Abnormal SMAD4 expression also plays an important role in the malignant progression of PDAC.MethodsWe investigated SMAD4 status in PDAC by immunohistochemical methods to explore the relationships between SMAD4 expression and clinicopathological features and then detected SMAD4 mutations by Sanger sequencing in 95 patients with PDAC to identify new mutation sites in PDAC. We further evaluated the effects of a missense mutation, Y353C, in the SMAD4 MH2 domain, on cell proliferation and migration in vitro.ResultsImmunohistochemistry showed that the expression of SMAD4 in PDAC carcinoma tissue was significantly lower than that in normal pancreatic tissue, and negative SMAD4 expression was closely related to tumour diameter, staging, lymph node metastasis and differentiation. Sanger sequencing analysis showed that the rate of SMAD4 mutation was 11.8% in 85 PDAC cases, and the novel SMAD4 Y353C missense mutation identified in this study promoted cell migration and invasion without affecting cell proliferation in vitro. Furthermore, SMAD4 Y353C resulted in reduced expression of E-cadherin and increased expression of Vimentin compared with wild-type SMAD4 overexpression.ConclusionThis study supports the key role of SMAD4 as a tumour suppressor gene in PDAC and shows that SMAD4 Y353C is associated with poor progression of PDAC.

1102 A Novel Plasma Based Metabolic Biomarker for the Differentiation of Pancreatic Ductal Adenocarcinoma Carcinoma (PDAC) From Chronic Pancreatitis (CP)

1102 A Novel Plasma Based Metabolic Biomarker for the Differentiation of Pancreatic Ductal Adenocarcinoma Carcinoma (PDAC) From Chronic Pancreatitis (CP)