Yan-Miao Huo

Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients’ clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.

Influence of Perineural Invasion on Survival and Recurrence in Patients with Resected Pancreatic Cancer

BACKGROUND Perineural invasion (PNI) has been reported as one of the sources of locoregional recurrence in resected pancreatic cancer (PC). However the impact of PNI in resected pancreatic cancer remains controversial. The purpose of this study was to determine the association between PNI status and clinical outcomes. METHODS Publications were identified which assessed prognostic significance of PNI status in resected pancreatic cancer up to February 2013. A meta-analysis was performed to clarify the association between PNI status and clinical outcomes. RESULTS A total of 21 studies met the inclusion criteria, covering 4,459 cases. Analysis of these data showed that intrapancreatic PNI was correlated with reduced overall survival only in resected pancreatic ductal adenocarcinoma (PDAC) patients (HR=1.982, 95%CI: 1.526-2.574, p=0.000). Extrapancreatic PNI was correlated with reduced overall survival in all resected pancreatic cancer patients (HR=1.748, 95%CI: 1.372- 2.228, p=0.000). Moreover, intrapancreatic PNI status may be associated with tumor recurrence in all resected pancreatic cancer patients (HR=2.714, 95%CI: 1.885-3.906, p=0.000). CONCLUSION PNI was an independent and poor prognostic factor in resected PDAC patients. Moreover, intrapancreatic PNI status may be associated with tumor recurrence.

High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma

BackgroundDiscoidin domain receptors 1 (DDR1), a subtype of DDRs, has been reported as a critical modulator of cellular morphogenesis, differentiation, migration and invasion.Methods and resultsIn this study, we investigated the expression of DDR1 and its clinical association in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). Across a cohort of 30 patients, we examined DDR1 expression in paired PDAC and corresponding adjacent non-tumor tissues by real-time quantitative PCR (RT-qPCR), or western blotting. DDR1 expression is significantly higher in PDAC, as compared to normal adjacent tissue, confirming results from the Oncomine databases. We validated DDR1 expression by immunohistochemistry across a non-overlapping cohort of 205 PDAC specimens. Kaplan-Meier survival curves indicate that increased expression of DDR1 is associated with a poor prognosis in PDAC patients (P = 0.013). Multivariate Cox regression analysis identified DDR1 expression, age, N classification and liver metastasis as independent prognostic factors in PDAC.ConclusionsThis study demonstrated that DDR1 can well serve as a novel prognostic biomarker in PDAC.

Clinicopathological, treatment, and prognosis study of 43 gastric neuroendocrine carcinomas

AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas (G-NECs) which occur rarely but are highly malignant and clinically challenging. METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria. RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half (48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases (72.09%), and liver metastasis was found in 6 cases (13.95%). Follow-up information was got for 40 patients. Twenty-three die of this disease with a median survival of 31 mo (range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR (30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence. CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.

Decreased LKB1 predicts poor prognosis in Pancreatic Ductal Adenocarcinoma

Liver kinase B1 (LKB1) has been identified as a critical modulator involved in cell proliferation and polarity. The purpose of the current study was to characterize the expression pattern of LKB1 and assess the clinical significance of LKB1 expression in pancreatic ductal adenocarcinoma (PDAC) patients. LKB1 mRNA expression which was analyzed in 32 PDAC lesions and matched non-tumor tissues, was downregulated in 50% (16/32) of PDAC lesions. Similar results were also obtained by analyzing three independent datasets from Oncomine. Protein expression of LKB1 was significantly reduced in 6 PDAC cell lines and downregulated in 31.3% (10/32) of PDAC lesions compared to matched non-tumorous tissues, as determined by Western blot analysis. Additionally, tissue microarray containing 205 PDAC specimens was evaluated for LKB1 expression by IHC and demonstrated that reduced expression of LKB1 in 17.6% (36/205) of PDAC tissues was significantly correlated with clinical stage, T classification, N classification, liver metastasis and vascular invasion. Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of PDAC and found that LKB1 protein expression was one of the independent prognostic factors for overall survival of PDAC patients.

Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer.

Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients’ TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.

Effect of CD74 on the prognosis of patients with resectable pancreatic cancer

BACKGROUND CD74 is known as a type II transmembrane glycoprotein that is associated with the major histocompatibility complex class II alpha and beta chains. Recent studies have demonstrated that the expression of CD74 is also linked to some forms of tumors. The present study was to assess the effect of CD74 expression on the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC). METHODS Forty-six patients who had received a curative resection of primary PDAC and postoperative chemotherapy were included in this study. Immunohistochemical staining was conducted of CD74 on paraffin-embedded tumor sample slices. The patients were grouped according to CD74 staining: CD74 (-): CD74 positive tumor cells<25%; and CD74 (+): CD74 positive tumor cells ≥25%. The correlation of CD74 expression level with clinicopathological features and cumulative survival rate was calculated. RESULTS The numbers of CD74 (+) and (-) patients were 32 and 14, respectively. CD74 (+) patients showed a high rate of perineural invasion (P=0.007). The 3- and 5-year cumulative survival rates of CD74 (-) patients were significantly higher than those of CD74 (+) patients (62% and 41% vs 9% and 0%, P=0.000). Multivariate analysis showed that CD74 expression and lymphatic permeation were the independent prognostic indicators. CONCLUSIONS The overexpression of CD74 is a key factor associated with perineural invasion. Lower-stage (I and II) PDAC patients with CD74 overexpression have a poor prognosis even if they receive a curative resection. CD74 can be used as a prognostic indicator for resectable PDAC.

High Expression of FAM83B Predicts Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma and Correlates with Cell Cycle and Cell Proliferation

FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. Whats more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. Its of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.

IL-22RA1/ STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer

Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR.

Efficacy of Neo-Adjuvant Chemoradiotherapy for Resectable Pancreatic Adenocarcinoma: A PRISMA-Compliant Meta-Analysis and Systematic Review.

AbstractWe have conducted a meta-analysis and systematic review to determine the overall survival, mortality rate, and complete resection rate of neo-adjuvant chemoradiotherapy (CRT) compared with pancreaticoduodenectomy alone in patients with pancreatic adenocarcinoma. Whether neo-adjuvant CRT is beneficial in the treatment of resectable pancreatic cancer or not, it is still a controversial issue.Medline and Cochrane were searched with relevant terms. Eight studies with a total of 833 participants were selected. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.The analysis revealed neo-adjuvant group may have a benefit in the overall survival, as compared with the resection group, although it did not reach statistical significance (pooled hazard ratio = 0.87, 95% confidence interval [CI] = 0.75–1.00, P = 0.051). We found no difference in the in-hospital mortality rate (pooled odds ratio [OR] = 1.27, 95% CI = 0.35–4.58, P = 0.710). The complete resection rate was significantly higher in the neo-adjuvant group than in the resection group (pooled OR = 2.39, 95% CI = 1.21–4.74, P = 0.012).This meta-analysis found that there was no significant difference in the overall survival between patients treated with neo-adjuvant CRT or pancreaticduodenectomy.