| 1. |
- Ansari, Daniel, et al.
(författare)
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Proteomic and genomic profiling of pancreatic cancer
- 2019
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Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 35:4, s. 333-343
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer.
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| 2. |
- Ansari, Daniel, et al.
(författare)
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The hippo signaling pathway in pancreatic cancer
- 2019
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 39:7, s. 3317-3321
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Forskningsöversikt (refereegranskat)abstract
- Hippo signaling is a key regulator of organ size, tissue hemostasis and regeneration. Dysregulation of the Hippo pathway has been recognized in a variety of human cancers, including pancreatic cancer. YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the two major downstream effectors of the Hippo pathway. YAP and TAZ have been found to promote pancreatic tumor development and progression, even in the absence of mutant Kirsten RAS (KRAS). Pancreatic cancer is associated with an abundant stromal reaction leading to tumor growth and immune escape. It has been found that YAP and TAZ modulate behavior of pancreatic stellate cells and recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. Moreover, YAP and TAZ are associated with chemoresistance and poor prognosis in pancreatic cancer. This review dissects the role of Hippo signaling in pancreatic cancer, focusing on molecular mechanisms and prospects for future intervention.
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| 3. |
- Byrling, Johannes, et al.
(författare)
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Mass spectrometry-based analysis of formalin-fixed, paraffin-embedded distal cholangiocarcinoma identifies stromal thrombospondin-2 as a potential prognostic marker
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Distal cholangiocarcinoma is an aggressive malignancy with a dismal prognosis. Diagnostic and prognostic biomarkers for distal cholangiocarcinoma are lacking. The aim of the present study was to identify differentially expressed proteins between distal cholangiocarcinoma and normal bile duct samples. Methods: A workflow utilizing discovery mass spectrometry and verification by parallel reaction monitoring was used to analyze surgically resected formalin-fixed, paraffin-embedded samples from distal cholangiocarcinoma patients and normal bile duct samples. Bioinformatic analysis was used for functional annotation and pathway analysis. Immunohistochemistry was performed to validate the expression of thrombospondin-2 and investigate its association with survival. Results: In the discovery study, a total of 3057 proteins were identified. Eighty-seven proteins were found to be differentially expressed (q < 0.05 and fold change ≥ 2 or ≤ 0.5); 31 proteins were upregulated and 56 were downregulated in the distal cholangiocarcinoma samples compared to controls. Bioinformatic analysis revealed an abundance of differentially expressed proteins associated with the tumor reactive stroma. Parallel reaction monitoring verified 28 proteins as upregulated and 18 as downregulated in distal cholangiocarcinoma samples compared to controls. Immunohistochemical validation revealed thrombospondin-2 to be upregulated in distal cholangiocarcinoma epithelial and stromal compartments. In paired lymph node metastases samples, thrombospondin-2 expression was significantly lower; however, stromal thrombospondin-2 expression was still frequent (72%). Stromal thrombospondin-2 was an independent predictor of poor disease-free survival (HR 3.95, 95% CI 1.09-14.3; P = 0.037). Conclusion: Several proteins without prior association with distal cholangiocarcinoma biology were identified and verified as differentially expressed between distal cholangiocarcinoma and normal bile duct samples. These proteins can be further evaluated to elucidate their biomarker potential and role in distal cholangiocarcinoma carcinogenesis. Stromal thrombospondin-2 is a potential prognostic marker in distal cholangiocarcinoma.
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| 4. |
- Hu, Dingyuan, et al.
(författare)
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Calcium-activated chloride channel regulator 1 as a prognostic biomarker in pancreatic ductal adenocarcinoma
- 2018
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In a previous study utilizing mass spectrometry-based proteomics, we identified calcium-activated chloride channel regulator 1 (CLCA1) as a potential tumor suppressor in pancreatic cancer and the expression was inversely correlated with patient survival. The aim of the study was to further validate the prognostic significance of CLCA1 in pancreatic cancer. METHODS: CLCA1 expression was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic ductal adenocarcinoma that underwent surgical resection at Skåne University Hospital, Sweden. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between CLCA1 and clinicopathological factors and survival. RESULTS: CLCA1 expression was denoted as positive in 90 tumors (64.3%), with positive staining being limited to the tumor cells. There were no significant association between CLCA1 expression and established clinicopathological parameters. Low CLCA1 expression correlated significantly with shorter disease-free survival (11.9 vs 17.5 months, P = 0.042). Multivariable Cox regression analysis confirmed the results (HR 0.61, 95% CI-0.40-0.92, P = 0.019). CONCLUSIONS: Low CLCA1 expression is an independent factor of poor disease-free survival in pancreatic cancer.
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| 5. |
- Hu, Dingyuan, et al.
(författare)
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Galectin 4 is a biomarker for early recurrence and death after surgical resection for pancreatic ductal adenocarcinoma
- 2019
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 54:1, s. 95-100
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Tidskriftsartikel (refereegranskat)abstract
- Background: Galectins are a group of carbohydrate-binding proteins that are involved in neoplastic development and progression. In a previous mass spectrometry-based study, we identified galectin 4 as a down-regulated protein in short-term survivors of pancreatic cancer. This study was performed to validate the prognostic value of galectin 4 in a larger cohort of pancreatic cancer patients undergoing surgical resection. Methods: Galectin 4 expression was evaluated by tissue microarrays and immunohistochemistry in 140 patients with surgically resected pancreatic cancer. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between galectin 4 and survival. Results: Galectin 4 staining expression was positive in 111 cases (79.3%). The expression of galectin 4 was significantly associated with tumor size (p =.008) and differentiation (p =.001). Galectin 4 expression was significantly correlated with disease recurrence within 1 year of surgery (adjusted HR 0.485, p =.027). There was also a significant association between galectin 4 and overall survival at 1 year (adjusted HR 0.482, p =.047) and at 3 years (adjusted HR 0.550, p =.025). Conclusion: Galectin 4 expression is a novel biomarker for early recurrence and mortality after surgical resection for pancreatic cancer.
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| 6. |
- Hu, Dingyuan
(författare)
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Identification of tissue biomarkers of prognostic significance in pancreatic cancer
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Pancreatic cancer is the third leading cause of cancer-related mortality. Lack of early detection strategies and therapeutic resistance are main contributors to the poor prognosis. Unfortunately, there are no tissue biomarkers available for the prognosis of pancreatic cancer in routine clinical use.Aim: To identify and validate novel tissue biomarkers for the prognosis of pancreatic cancer.Methods: A mass spectrometry-based proteomic approach was applied to formalin-fixed paraffin-embedded specimens from surgically resected pancreatic cancer in 9 patients with short survival (<12 months) and 10 patients with long survival (>45 months). The dysregulated biomarkers were further verified by targeted proteomics, parallel reaction monitoring. Finally, we evaluated prognostic candidates (CLCA1, galectin 4, P4HA2, PRTN3 and fibronectin) by tissue microarray and immunohistochemistry in a larger cohort of patients with pancreatic cancer who underwent surgical resection (n=144). Bioinformatic analysis was exploited to assess pathways and networks linked to the prognosis. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between biomarkers and survival.Results/Conclusion: A total of 24 and 147 proteins were significantly upregulated in patients with short survival and long survival, respectively. Bioinformatic analysis linked proteins representing “activated stroma factors” and “basal tumor factors” to poor prognosis and highlighted TCF1 and CTNNB1 as possible upstream regulators. By targeted proteomics, seven proteins were verified to be upregulated in patients with short survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with long survival, including EPCAM, galectin 4, VIL1, CLCA1 and TPPP3 (I). By immunohistochemical validation, we found that low CLCA1 expression correlated significantly with shorter disease-free survival (II). Furthermore, galectin 4 expression significantly correlated with disease recurrence within 1 year of surgery and with overall survival at 1- and 3-year (III). Besides, a low P4HA2 and high PRTN3 expression pattern correlated with shorter disease-free survival and overall survival (IV). Finally, high stromal FN1 expression was associated with aggressive tumor characteristics in patients with resected pancreatic cancer, although it was not associated with survival (V).
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| 7. |
- Hu, Dingyuan, et al.
(författare)
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Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer
- 2019
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 54:2, s. 246-251
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Tidskriftsartikel (refereegranskat)abstract
- Background: The tumor microenvironment in pancreatic cancer has a multifaceted role in disease development and progression. Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) and proteinase 3 (PRTN3) are involved in the synthesis and degradation of collagen in the tumor microenvironment and have been identified as prognostic biomarker candidates for pancreatic cancer in our previous mass spectro-metric study. This study aimed at validating prognostic performance of P4HA2 and PRTN3 in a larger cohort of patients. Methods: The expression of P4HA2 and PRTN3 was evaluated with tissue microarrays and immunohis-tochemistry in 140 patients with pancreatic cancer who underwent surgical resection. Kaplan–Meier and Cox proportional hazards regression modeling were used to explore the association of P4HA2 and PRTN3, either separately or combined, with clinicopathological factors and survival. Results: Most tumors were positive for P4HA2 (133/140, 95%), whereas 77 tumors (55%) were positive for PRTN3. Expression levels of P4HA2 and PRTN3 did not separately correlate with disease-free or overall survival, in either uni-or multivariable analysis. However, a low P4HA2 and high PRTN3 expression correlated with shorter disease-free survival (median 7.0 vs. 13.4 months, adjusted HR 3.24, 95% CI: 1.13–9.25, p ¼.028) and overall survival (median 8.5 vs. 25.8 months, adjusted HR 8.14, 95% CI: 3.41–19.44, p <.001). Conclusion: Our data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. The tumoral expression of PRTN3 reinforces the therapeutic potential of PR1-targeting immunotherapy in pancreatic cancer.
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| 8. |
- Hu, Dingyuan, et al.
(författare)
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Proteomic analyses identify prognostic biomarkers for pancreatic ductal adenocarcinoma
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:11, s. 9789-9807
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Here we show that shotgun and targeted protein sequencing can be used to identify potential prognostic biomarkers in formalin-fixed paraffin-embedded specimens from 9 patients with PDAC with "short" survival (< 12 months) and 10 patients with "long" survival ( > 45 months) undergoing surgical resection. A total of 24 and 147 proteins were significantly upregulated [fold change ≥2 or ≤0.5 and P < 0.05; or different detection frequencies (≥5 samples)] in patients with "short" survival (including GLUT1) and "long" survival (including C9orf64, FAM96A, CDH1 and CDH17), respectively. STRING analysis of these proteins indicated a tight protein-protein interaction network centered on TP53. Ingenuity pathway analysis linked proteins representing "activated stroma factors" and "basal tumor factors" to poor prognosis of PDAC. It also highlighted TCF1 and CTNNB1 as possible upstream regulators. Further parallel reaction monitoring verified that seven proteins were upregulated in patients with "short" survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with "long" survival, including EPCAM, LGALS4, VIL1, CLCA1 and TPPP3. Thus, we verified 25 protein biomarker candidates for PDAC prognosis at the tissue level. Furthermore, an activated stroma status and protein-protein interactions with TP53 might be linked to poor prognosis of PDAC.
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| 9. |
- Hu, Dingyuan, et al.
(författare)
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Stromal fibronectin expression in patients with resected pancreatic ductal adenocarcinoma
- 2019
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Ingår i: World Journal of Surgical Oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense stroma, which has a fundamental role in tumor progression. Fibronectin (FN1) is the main constituent of the tumor stroma in pancreatic cancer. This study aimed to explore the association between FN1 and clinicopathological characteristics and disease survival. Methods: Formalin-fixed paraffin-embedded tissue samples from 138 patients with PDAC were constructed into a tissue microarray, followed by immunohistochemical analysis with a recombinant monoclonal FN1 antibody. Chi-square test or Fisher's exact test were used for comparison of FN1 expression and relevant clinicopathological parameters. Kaplan-Meier survival curves and Cox regression analyses were used to assess the association between FN1 and survival. Results: FN1 was detected in the stromal compartment in most cases (117/138, 84.8%). Compared to the low FN1 expression group, the high FN1 expression group had significantly larger tumor size (P = 0.002), more advanced T stage (P = 0.039) and N stage (P = 0.009), and also worse AJCC stage (P = 0.003). However, stromal FN1 expression was not associated with disease-free survival or overall survival. Conclusions: This study suggests that high stromal FN1 expression is associated with aggressive tumor characteristics in patients with resected PDAC. However, no association between FN1 expression and survival was found.
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| 10. |
- Hu, Dingyuan, et al.
(författare)
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The Emerging Role of Calcium-activated Chloride Channel Regulator 1 in Cancer
- 2019
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 1791-7530 .- 0250-7005. ; 39:4, s. 1661-1666
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Forskningsöversikt (refereegranskat)abstract
- Calcium-activated chloride channel regulator 1 (CLCA1) belongs to a group of secreted self-cleaving proteins, which activate calcium-dependent chloride channels. CLCA1 has been shown to participate in the pathogenesis of inflammatory airway diseases such as asthma. Recently, additional functions of CLCA1 have been unveiled, including its metalloprotease property and involvement in mucus homeostasis and immune modulation. Emerging evidence suggests that CLCA1 may also be involved in the pathophysiology of colorectal, pancreatic and ovarian cancer. There is growing interest in utilizing CLCA1 as a diagnostic, prognostic and predictive biomarker, as well as a potential therapeutic target. In this review, the functional role of CLCA1, with a particular focus on cancer, is described.
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