Diagnostic biomarkers for the early diagnosis of pancreatic cancer are needed to improve prognosis for this disease. The aim of this study was to investigate differences in the expression of four messenger RNAs (mRNAs: CCDC88A,ARF6, Vav3, and WASF2) and five small nucleolar RNAs (snoRNAs: SNORA14B,SNORA18,SNORA25,SNORA74A, and SNORD22) in serum of patients with pancreatic cancer and control participants for use in the diagnosis of pancreatic cancer. Results were compared with the expression of sialylated Lewis (a) blood group antigen CA19‐9, the standard clinical tumor biomarker. Reverse transcription quantitative real‐time PCR showed that all of the mRNAs and snoRNAs, except CCDC88A, were encapsulated in exosomes and secreted from cultured pancreatic cancer cells, and present in cell culture medium. In a discovery‐stage clinical study involving 27 pancreatic cancer patients and 13 controls, the area under the receiver operating characteristic curve (AUC) of two mRNAs (WASF2 and ARF6) and two snoRNAs (SNORA74A and SNORA25) was > 0.9 for distinguishing pancreatic cancer patients from controls; the AUC of CA19‐9 was 0.897. Comparing serum levels of WASF2,ARF6,SNORA74A,SNORA25, and CA19‐9 revealed that levels of WASF2 were the most highly correlated with the risk of pancreatic cancer. The AUCs of WASF2,ARF6,SNORA74A, and SNORA25 in serum from patients in the early stages of pancreatic cancer (stages 0, I, and IIA) were > 0.9, compared with an AUC of 0.93 for the level of CA19‐9. The results of this study suggest that WASF2,ARF6,SNORA74A, and SNORA25 may be useful tools for the early detection of pancreatic cancer. Monitoring serum levels of WASF2 mRNA may be particularly useful, as it was the most highly correlated with pancreatic cancer risk.

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genes encode transcription factors that function as sequence-specific transcription factors that are involved in cellular proliferation, differentiation, and death. The aim of this study was to investigate the role of a HOX family protein, HOXB7, in the motility and invasiveness of pancreatic cancer cells. We previously identified a transcript that is one of a number of transcripts that are preferentially translated in membrane protrusions in pancreatic cancer cells. Immunocytochemistry showed that HOXB7 was localized to the cell protrusions of migrating pancreatic cancer cells. Knockdown of HOXB7 by transfection with-specific siRNA decreased these protrusions and inhibited the motility and invasiveness of the cells. Transfection of a HOXB7-rescue construct into the HOXB7-knockdown cells restored peripheral actin structures in cell protrusions and abrogated the HOXB7 knockdown-induced decrease in cell protrusions. It is generally accepted that the Rho family of GTPases regulate the organization of actin filaments and contribute to the formation of cell protrusions. The levels of the active Rho GTPases were not influenced by HOXB7 in the cells; however, HOXB7 knockdown decreased the level of phosphorylated ERK1/2. This inactivation of ERK1/2 decreased cell protrusions, thereby inhibiting the invasiveness of pancreatic cancer cells. Further investigation showed that HOXB7/ERK1/2 signaling selectively stimulated JNK and HSP27 phosphorylation and thereby increased the motility and invasiveness of pancreatic cancer cells. These results suggested that HOXB7 stimulates ERK1/2 phosphorylation and provided evidence that HOXB7, besides its role in transcriptional regulation, also promotes cell motility and invasiveness.

We report the use of small interfering RNAs (siRNAs) against ARHGEF4 , CCDC88A , LAMTOR2 , mTOR , NUP85 , and WASF2 and folic acid (FA)-modified polyethylene glycol (PEG)-chitosan oligosaccharide lactate (COL) nanoparticles for targeting, imaging, delivery, gene silencing, and inhibition of invasiveness and metastasis in an orthotopic xenograft model. In vitro assays revealed that these siRNA-FA-PEG-COL nanoparticles were specifically inserted into pancreatic cancer cells compared to immortalized normal pancreatic epithelial cells and knocked down expression of the corresponding targets in pancreatic cancer cells. Cell motility and invasion were significantly inhibited by adding target siRNA-FA-PEG-COL nanoparticles into the culture medium. In vivo mouse experiments confirmed that when intravenously delivered, these siRNA-FA-PEG-COL nanoparticles became incorporated into human pancreatic cancer cells in mouse pancreatic tumors. Little accumulation was seen in the normal pancreas and vital organs. All target siRNA-FA-PEG-COL nanoparticles significantly inhibited retroperitoneal invasion. The siRNA-FA-PEG-COL nanoparticles against LAMTOR2 , mTOR , and NUP85 , which strongly inhibited retroperitoneal invasion and significantly inhibited peritoneal dissemination compared to the other nanoparticles, improved prognosis of the mice. Our results imply that siRNA-FA-PEG-COL nanoparticles against these six targets could have great potential as biodegradable drug carriers. In particular, siRNA nanoparticles against LAMTOR2 , mTOR , and NUP85 may hold significant clinical promise.

BackgroundThe aim of this study was to investigate the use of podocalyxin (PODXL) and secretoglobin family 1D, member 2 (SCGB1D2) expressions in whole blood as diagnostic biomarkers to distinguish between patients with pancreatic cancer and control participants, in comparison with serum cancer antigen 19-9 (CA19-9), which is the current clinical standard.Patients and methodsFlow cytometric analysis was performed to determine the expressions of PODXL and SCGB1D2 on the surface of cultured pancreatic cancer cells. Immunoblotting was performed to determine whether PODXL and SCGB1D2 were detectable in the media of cultured pancreatic cancer cells. A discovery-stage clinical study was performed in a cohort of 23 patients with pancreatic cancer and 51 control individuals without pancreatic disease who had been treated in the Department of Gastroenterology and Hepatology at Kochi Medical School Hospital from April 2014 to January 2016. Serum PODXL and SCGB1D2 levels were measured by enzyme-linked immunosorbent assay (ELISA).ResultsPODXL and SCGB1D2 accumulated in the protrusions of cultured pancreatic cancer cells, and they were detectable both on the cell surface and in the cultured media from these cells. The discovery-stage clinical study showed that the area under the receiver-operating characteristic curve (AUC) was 0.96 (95% confidence interval [CI] 0.91–1.000) for PODXL, 0.80 (95% CI 0.67–0.94) for SCGB1D2, and 0.78 (95% CI 0.66–0.90) for CA19-9. The AUC for PODXL was thus significantly higher than that for CA19-9 (P = 0.006). The combination of SCGB1D2 with CA19-9 did not significantly increase the AUC (0.83; 95% CI 0.70–0.96) compared with the AUC for either SCGB1D2 or CA19-9 alone (P = 0.563).ConclusionPODXL may be a novel, non-invasive diagnostic biomarker for the detection of pancreatic cancer.