Chenlei Wen

Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer

BackgroundPancreatic cancer, one of the top two most fatal cancers, is characterized by a desmoplastic reaction that creates a dense microenvironment, promoting hypoxia and inducing the epithelial-to-mesenchymal transition (EMT) to facilitate invasion and metastasis. Recent evidence indicates that the long noncoding RNA NORAD may be a potential oncogenic gene and that this lncRNA is significantly upregulated during hypoxia. However, the overall biological role and clinical significance of NORAD remains largely unknown.MethodsNORAD expression was measured in 33 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of NORAD on pancreatic cancer cells were studied by overexpression and knockdown in vitro. Insights into the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatics analyses and luciferase assays. In vivo, metastatic potential was identified using an orthotopic model of PDAC and quantified using bioluminescent signals. Alterations in RhoA expression and EMT levels were identified and verified by immunohistochemistry and Western blotting.ResultsNORAD is highly expressed in pancreatic cancer tissues and upregulated in hypoxic conditions. NORAD upregulation is correlated with shorter overall survival in pancreatic cancer patients. Furthermore, NORAD overexpression promoted the migration and invasion of pancreatic carcinoma cells, while NORAD depletion inhibited EMT and metastasis in vitro and in vivo. In particular, NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p, thereby promoting EMT.ConclusionsElevated expression of NORAD in pancreatic cancer tissues is linked to poor prognosis and may confer a malignant phenotype upon tumor cells. NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p. This finding may contribute to a better understanding of the role played by lncRNAs in hypoxia-induced EMT and provide a potential novel diagnostic and therapeutic target for pancreatic cancer.

mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer

Pancreatic cancer is one of the most lethal malignancies worldwide. To illustrate the pathogenic mechanism(s), we looked into the expression and function of miR-329 associated with pancreatic cancer development. It was found that miR-329 expression was downregulated in the pancreatic cancer patients who demonstrated significantly shorter overall survival than the patients having upregulated expression. Also, more advanced pT stage cases were observed in the low miR-329 expression group of patients. Interestingly, our studies uncovered that miR-329 overexpression inhibited proliferation and induced apoptosis of pancreatic cancer cells, in contrast the miR-329 inhibitor reversed this phenomenon dramatically. Additionally, overexpression of miR-329 significantly limited tumor growth in the xenograft model. In the mechanistic study, we identified GRB2 as a direct target of miR-329 in pancreatic cancer cells, and expression of GRB2 was inversely correlated with miR-329 expression in pancreatic cancer patients. Furthermore, GRB2 overexpression in cell line and xenograft model dramatically diminished miR-329 mediated anti-proliferation and apoptosis induction, indicating that GRB2/pERK pathway was mainly downregulated by miR-329 expression. In general, our study has shed light on miR-329 regulated mechanism and, miR-329/GRB2/pERK is potential to be targeted for pancreatic cancer management.

Melittin inhibits tumor growth and decreases resistance to gemcitabine by downregulating cholesterol pathway gene CLU in pancreatic ductal adenocarcinoma

Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment. For instance, the cholesterol pathway gene clusterin (CLU) was highly downregulated by melittin which also enhanced gemcitabine sensitivity in PDAC cells by inhibiting CLU expression. In contrast, overexpression of CLU significantly diminished melittin mediated tumor suppression and gemcitabine sensitization, suggesting that CLU is the target of melittin. Furthermore, in the xenograft mouse model, the combination therapy of melittin and gemcitabine is more efficacious for inhibiting PDAC tumor growth than either single regimen. Taken together, our study has indicated that melittin is capable of suppressing tumor growth and promoting gemcitabine sensitivity in PDAC by downregulating cholesterol pathway.

Modified protocol for enhanced recovery after surgery is beneficial for Chinese cancer patients undergoing pancreaticoduodenectomy

Radical surgical resection remains the only effective treatment for advanced pancreatic cancer. Effective protocols for recovery from post-operative complications that result in high rates of morbidity and mortality are therefore essential. The enhanced recovery after surgery (ERAS) protocol is an interdisciplinary multimodal concept based on modern anesthesia and analgesia combined with other fast rehabilitation parameters. It was first applied in the field of elective colorectal surgery, and eventually extended to several surgical diseases. In this study, we investigated the feasibility and safety of implementing the ERAS protocol in patients undergoing pancreaticoduodenectomy (PD). We randomly divided 159 patients who underwent PD into two groups who were managed using either ERAS or the conventional protocol. We observed that in those treated with the ERAS protocol several post-operative recovery factors were greatly improved, and there were no complications requiring readmission. We therefore propose that ERAS can improve post-operative recovery of PD patients and shorten the waiting time to chemotherapy, which may improve the overall survival of surgically treated pancreatic cancer patients.

Capture-based next-generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing.

Targeted therapies including monoclonal antibodies and small molecule inhibitors have dramatically changed the treatment of cancer over past 10 years. Their therapeutic advantages are more tumor specific and with less side effects. For precisely tailoring available targeted therapies to each individual or a subset of cancer patients, next‐generation sequencing (NGS) has been utilized as a promising diagnosis tool with its advantages of accuracy, sensitivity, and high throughput.

Robot-Assisted Middle Pancreatectomy for Elderly Patients: Our Initial Experience

Background The aim of this study was to evaluate the indications, safety, feasibility, and short- and long-term outcomes for elderly patients who underwent robot-assisted middle pancreatectomies (MPs). Material/Methods Ten patients (≥60 years) underwent robot-assisted middle pancreatectomies from 2012 to 2015. The perioperative data, including tumor size, operating time, rate of postoperative pancreatic fistula (POPF), postoperative morbidity, and other parameters, were analyzed. We collected and analyzed the follow-up information. Results The mean age of patients was 64.30 years (range, 60–73 years). The average tumor size was 2.61 cm. The 10 cases were all benign or low-grade malignant lesions. The mean operating time was 175.00 min. The mean blood loss was 113.00 ml with no blood transfusion needed. Postoperative fistulas developed in 5 patients; there were 2 Grade A fistulas and 3 grade B fistulas. There were 3 patients who underwent postoperative complications, including 2 Grade 1 or 2 complications and 1 Grade 3 complication. No reoperation and postoperative mortality occurred. The mean hospital stay was 19.91 days. After a median follow-up of 23 months, new onset of diabetes mellitus developed in 1 patient and none suffered from deterioration of previously diagnosed diabetes or exocrine insufficiency, and no tumor recurrence happened. Conclusions Robot-assisted middle pancreatectomy was safe and feasible for elderly people. It had low risk of exocrine or endocrine dysfunction and benefited patients’ long-term outcomes. Incidence of POPF was relatively high but we could prevent it from resulting in bad outcomes by scientific perioperative care and systemic treatment.

Preliminary experience of the robot‑assisted laparoscopic excision of a retroperitoneal mass: A case report

The aim of the present study was to report the initial clinical experience of adopting the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA, USA) to perform a retroperitoneal tumor resection. The patient was a 56-year-old female who presented with a five-year history of hypertension. Abdominal dynamic computed tomography (CT) and positron emission tomography-CT scans revealed a mass measuring ~6 cm in diameter that was located anterior to the abdominal aorta, and between the abdominal aorta and the inferior vena cava (at the level of the third lumbar vertebra). The tumor was excised via a five-port, robot-assisted, transperitoneal laparoscopic approach. Careful dissection of the tumor away from the abdominal aorta and the inferior vena cava was accomplished without resulting in major vascular injury. There were no complications and the patient was discharged in a good condition on the eleventh postoperative day. Pathological analysis of a tumor specimen demonstrated a benign pheochromocytoma (PHEO). During the three-month follow-up, no recurrence was identified through CT scans or measurement of the patient’s endocrine hormone levels. Thus, the da Vinci robot-assisted laparoscopic system may be safely employed in the treatment of extra-adrenal PHEOs that occur in difficult locations for which a laparoscopic surgical excision may be challenging.

Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance

Pancreatic cancer is one of the most fatal types of cancer and is associated with a dismal prognosis. Gemcitabine-based chemotherapy is clinically used for the treatment of advanced pancreatic cancer. However, many forms of pancreatic cancer have acquired resistance to gemcitabine. In order to prevent patients from suffering from the side effects of chemotherapy and to have the chance to receive more effective intervention, assessment of whether the patient pancreatic cancer cells are resistant to gemcitabine before clinical practice is crucial. Recently, patient-derived xenograft (PDX) models have been regarded as a practical approach for preclinical drug resistance test. In the present study, we harvested tumor specimens from 28 pancreatic cancer patients to establish PDX models. The tumor formation rate of the xenografts was 100%, several of which could be re-implanted in nude mice for more than 10 passages. Primary cells were further obtained from the PDX xenografts to determine their morphological features and evaluate their proliferation rate, migration capacity and angiopoietic ability. In addition, the sensitivities of the primary cells and PDX xenografts to gemcitabine were correlated with each other. When compared to the gemcitabine-sensitive cells, the gemcitabine-resistant cells had a higher level of MCF2L expression, suggesting that MCF2L plays an important role in gemcitabine resistance.