Shunrong Ji

RGD-conjugated albumin nanoparticles as a novel delivery vehicle in pancreatic cancer therapy

Integrin αvβ3 receptor is expressed on several types of cancer cells, including pancreatic cancer cells, and plays an important role in tumor growth and metastasis. The ability to target the integrin αvβ3 receptor on cancer cells increases the efficacy of targeted therapy and reduces the side effects. The aim of this study is to develop a novel arginine-glycine-aspartic acid (RGD) peptide-conjugated albumin nanoparticle to enhance the intracellular uptake of anticancer drug into the pancreatic cancer cells through receptor-mediated endocytosis. In cellular uptake studies, the fluorescent signal of RGD-conjugated BSANPs in BxPC3 cells was higher than that of BSANPs without RGD conjugation as determined by fluorescence spectrophotometer. We also found that BSANPs bound to BxPC3 cells in a time- and concentration-dependent manner. The uptake of RGD-conjugated BSANPs by pancreatic cancer cells was inhibited by an excess amount of free RGD peptide, indicating that the binding and/or uptake were mediated by the αvβ3 receptor. Furthermore, the nanoparticles were found to be located close to the nuclei by using laser scanning confocal microscopy. Besides, no significant in vitro cytotoxicity was observed as measured with MTT assay. Both in vitro and in vivo antitumor efficacy was improved by targeting gemcitabine-loaded nanoparticles to BxPC-3 cells using RGD peptides. Therefore, the RGD-conjugated BSANPs hold great potential as an effective drug delivery system to deliver therapeutic agents to pancreatic cancer.

ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer

F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-F-box (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.

LSD1 sustains pancreatic cancer growth via maintaining HIF1α-dependent glycolytic process

The histone demethylase LSD1 (lysine specific demethylase 1) plays an important role in the epigenetic regulation of gene transcription. Our study investigated the role of LSD1 in pancreatic cancer and demonstrated that LSD1 was significantly up-regulated in pancreatic cancer patient tissue samples, and elevated LSD1 protein levels positively correlated with overall survival of pancreatic cancer patients. Using in vitro and in vivo models, we demonstrated that knock-down of LSD1 repressed proliferation and tumorigenicity of pancreatic cancer cells. Mechanistically, our study demonstrated that LSD1 synergized with HIF1α (hypoxia inducible factor-1α) in maintaining glycolytic process, which fueled pancreatic cancer uncontrolled proliferation.

Quantum dots in cancer therapy

Introduction: Quantum dots (QDs) are nanometer-size luminescent semiconductor nanocrystals. Their unique optical properties, such as high brightness, long-term stability, simultaneous detection of multiple signals and tunable emission spectra, make them appealing as potential diagnostic and therapeutic systems in the field of oncology. Areas covered: This paper summarizes the recent progress of promising applications of QDs in cancer therapy, from the following aspects: identifying molecular targets, sentinel lymph-node mapping, surgical oncology, drug delivery and tracking, fluorescence resonance energy transfer and photodynamic therapy, personalized and predictive medicine, and multifunctional design and development. Limitations and toxicity issues related to QDs in living organisms are also discussed. Expert opinion: Bioconjugated QDs can be used to identify potential molecular biomarkers for cancer diagnosis, treatment and prognosis. They may allow the surgeon to map sentinel lymph nodes and perform a complete surgical resection. Their unique optical properties make them ideal donors of fluorescence resonance energy transfer and photodynamic therapy studies. Multifunctional QDs have become effective materials for synchronous cancer diagnosis, targeting and treatment. For QDs, toxicity remains the major barrier to clinical translation.

Up-Regulation of MBD1 Promotes Pancreatic Cancer Cell Epithelial-Mesenchymal Transition and Invasion by Epigenetic Down-Regulation of E-Cadherin

Methyl-CpG binding domain protein 1 (MBD1) has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression and development. It is also predicted that MBD1 might be involved in tumor development and progression. However, whether and how MBD1 is involved in tumorigenesis, especially in pancreatic cancer (PC), is currently unknown. We found that MBD1 was significantly up-regulated in PC tissues compared with the surrounding normal tissues according to RT-PCR data. Tissue microarray (TMA) based immunohistochemical study from 58 surgically resected PC specimens indicated that higher MBD1 expression correlated with lymph node metastasis and poor survival in PC patients. Gain- and loss-of-function studies in vitro validated MBD1 as a potent oncogene promoting PC cell invasion as well as epithelial-mesenchymal transition (EMT). Mechanistically, MBD1 is associated with Twist and NAD-dependent deacetylase sirtuin-1 (SIRT1), thereby forming the Twist-MBD1-SIRT1 complex on the CDH1 promoter, which resulted in reduced E-cadherin transcription activity and increased cell EMT ability. Significantly, targeting MBD1 reversed the EMT phenotype of PC and restored sensitivity to chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in PC invasion and metastasis by providing a molecular mechanism underlying MBD1-promoted EMT. Thus MBD1 may serve as a potential therapeutic target for PC.

FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin binding protein) axis in pancreatic cancer

Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras–Raf–MEK–ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways. Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc–dependent manner. Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950–60. ©2016 AACR.

Management of a malignant case of solid pseudopapillary tumor of pancreas: A case report and literature review

Solid pseudopapillary tumor of the pancreas is a rare neoplasm with low malignant potential, which affects predominantly young females. Only approximately 10% to 15% cases of solid pseudopapillary tumors (SPTs) are malignant. We present the case of a 57-year-old woman who developed malignant SPT of the pancreas. Meanwhile, a literature review was carried out. Some clinicopathological features and strategies of management of malignant SPT are presented. In general, surgical removal of the tumor even in case of metastases or recurrence offers an excellent prognosis. Chemotherapy and radiotherapy should be taken into consideration in patients with unresectable tumor.

ALDOA functions as an oncogene in the highly metastatic pancreatic cancer

Pancreatic cancer is an aggressive and devastating disease that is characterized by uncontrolled progression, invasiveness and resistance to conventional treatment. In the past decades, much effort has been given to cancer genetics and pathological classification of this disease. Our previous study has uncovered a subgroup of patients with poor outcome, which is characterized by serum signature of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL; however, the underlying biology mechanism remains poorly understood. By using high-throughput screening analysis, we analyzed gene expression signature in highly malignant patients with serum markers of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL. Multiple differentially expressed genes were identified, many of which were closely related with cancer metabolic changes. Treatment of pancreatic cancer cell lines PANC-1 with transforming growth factor-β (TGF-β), which was commonly used to induce metastasis, has uncovered that the glycolytic process and antioxidant response was up-regulated upon TGF-β stimulation. These results were consistent with the high-throughput screening analysis. Subsequent analysis indicated that among glycolytic genes, aldolase A (ALDOA) increased the most significantly upon TGF-β treatment. Further in vitro and in vivo results demonstrated that ALDOA was associated with proliferation and metastasis of pancreatic cancer cells. Moreover, ALDOA predicted poor prognosis of pancreatic cancer, partially due to its role in E-cadherin expression regulation, and the results were further validated by analysis of the correlation between ALDOA and E-cadherin expression in pancreatic cancer tissue samples. Mechanistically, the role of ALDOA in pancreatic cancer might attribute to its regulation of c-Myc, HIF1α and NRF2 (Nuclear Factor, Erythroid 2-Like 2), which were key regulators of glycolysis and antioxidant response control.

Noncoding RNAs as potential biomarkers to predict the outcome in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), a common digestive system cancer, is highly malignant and has a poor disease outcome. Currently, all available examination and detection methods cannot accurately predict the clinical outcome. Therefore, it is extremely important to identify novel molecular biomarkers for personalized medication and to significantly improve the overall outcome. The “noncoding RNAs” (ncRNAs) are a group of RNAs that do not code for proteins, and they are categorized as structural RNAs and regulatory RNAs. It has been shown that microRNAs and long ncRNAs function as regulatory RNAs to affect the progression of various diseases. Many studies have confirmed a role for ncRNAs in the progression of PDAC during the last few years. Because of the significant role of ncRNAs in PDAC, ncRNA profiling may be used to predict PDAC outcome with high accuracy. This review comprehensively analyzes the value of ncRNAs as potential biomarkers to predict the outcome in PDAC and the possible mechanisms thereof.

Silencing of MBD1 reverses pancreatic cancer therapy resistance through inhibition of DNA damage repair

High resistance to traditional chemo- and radiotherapies contributes to the poor prognosis of pancreatic cancer (PC). Methyl-CpG binding domain protein 1 (MBD1), which plays an important role in disease progression, contributes to the drug resistance of PC cells; however, the mechanism underlying the drug resistance endowed by MBD1 remains unknown. In this study, we found that MBD1 was recruited to DNA damage sites under DNA damage conditions. Silencing of MBD1 significantly impaired activation of the DNA damage checkpoint response and inhibited DNA repair capacity. MBD1 binds mediator of DNA damage checkpoint protein 1 (MDC1), which is induced by radiation and regulates NBS1 activation in the presence of DNA damage repair. Knockdown of MBD1 significantly increased the sensitivity of cells to radiation and cisplatin (diamindichloridoplatin, DDP) in vitro. Importantly, the function of MBD1 in regulating chemoradioresistance is also partially dependent on DNA damage repair. Thus, we hypothesize that MBD1 may promote PC chemoradioresistance by regulating PC cell fate in the presence of DNA damage. Collectively, these findings reveal an important function of MBD1 in DNA repair and mediation of chemoradioresistance of cancer cells. Moreover, this study suggests that MBD1 is a promising molecular target for sensitizing resistant PC tumor cells to chemoradiotherapy.