Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling.

BACKGROUND: The epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of ß-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling. METHODS: Gemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated. RESULTS: LRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling. CONCLUSIONS: Our findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling.

[A Case of Squamous Cell Carcinoma of the Lung from Gastrointestinal Perforation Due to Small Intestinal Metastasis].

An 80s male, with a medical history of hypertension, hyperuricemia, and atrial fibrillation, visited our emergency outpatient department with vomiting and diarrhea as the chief complaint in August 2017. The blood examination revealed a high level of inflammatory reaction. The plain abdominal CT revealed fluid retention contacting the small intestine and intraabdominal free gas. We diagnosed the case as a small intestinal perforation, following which we performed emergency surgery. The small intestine was perforated, and an abscess cavity was formed between the transverse mesocolon and mesentery proper. Thus, the abscess was removed, and about 30 cm of the small intestine, including the perforated site, was resected, followed by the reconstruction. The resected specimens revealed squamous cell carcinoma at the small intestinal perforated site. Lung squamous cell carcinoma was diagnosed by subsequent chest CT and immunostaining. We administered 3 courses of chemotherapy combined with carboplatin and albumin-bound paclitaxel. Although the effect was partially observed, interstitial pneumonia occurred, which was inferred to be drug-induced. The patient died in 195 days following the surgery. Herein, we reported a case of lung cancer, which was diagnosed on the detection of gastrointestinal perforation caused by a small intestinal metastasis.

G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner.

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.

Impacts of negatively charged colloidal clay particles on photoisomerization of both anionic and cationic azobenzene molecules.

Although smectite-type clays are used as heterogeneous media for photofunctional guest molecules, the guest species are limited to cationic or polar molecules because of the intrinsic negative electric charges of clay particles. Nevertheless, in this study, aqueous clay colloids are reported to affect the photoisomerization kinetics of anionic and cationic azobenzene molecules dissolved in the colloids. Under UV-light irradiation, the clay colloids decelerate trans-to-cis isomerization, while under visible-light irradiation, the clay colloids accelerate cis-to-trans isomerization. In addition, the sol-gel transition of clay colloids affects the kinetics. The results considerably expand the applicability of clay colloids as matrixes for functional organic species.

MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells.

OBJECTIVES: Platelet-derived growth factor receptor beta (PDGFRß) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRß, on the interaction between PCCs and PSCs. METHODS: In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRß and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. RESULTS: In PSCs, PDGFRß and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. CONCLUSIONS: The PDGFRß and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.

Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/ß-catenin signaling pathway.

The canonical Wnt/ß-catenin signaling pathway has been shown to promote the epithelial-mesenchymal transition (EMT), which is a crucial process in multiple embryonic developmental processes and the progression of carcinomas. We recently provided evidence that leucine-rich repeat flightless-1-interacting protein 1 (LRRFIP1) promotes cancer metastasis and invasion. In the present study, we identified the signaling elements targeted by LRRFIP1 for promotion of the EMT in pancreatic and lung cancer. LRRFIP1 silencing reversed the EMT, as shown by increased expression of E-cadherin (an epithelial marker) and decreased expression of vimentin (a mesenchymal marker). Silencing of LRRFIP1 up-regulated phosphorylation of ß-catenin and decreased its nuclear localization by targeting the ß-catenin destruction complex. The expression of ß-catenin and E-cadherin in the plasma membrane fraction was increased in LRRFIP1 silenced cancer cells, and the migration and invasion capabilities were strongly inhibited. In addition, this protein was highly expressed at the invasion front of malignant tissue collected from pancreatic cancer patients. Consequently, our data strongly suggested that LRRFIP1 played an important role in the invasion of carcinoma cells. Our data provide experimental evidence that LRRFIP1 is an attractive candidate for targeted therapy in human cancers.