SMAD4 Y353C promotes the progression of PDAC

Wang, Zusen; Li, Yongxing; Zhan, Shixiong; Zhang, Lu; Zhang, Shun; Tang, Qian; Li, Miaomiao; Tan, Zhen; Liu, Shiguo; Xing, Xiaoming

doi:10.1186/s12885-019-6251-7

Cited by 19 publications

(22 citation statements)

References 52 publications

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“…We tested this in vitro and found that miR-483-3p promoted cell migration and invasion in transwell assays. These findings are consistent with known functions of the putative miR-483-3p target SMAD4 53,54 and further suggest that miR-483-3p may play a key role in PDAC progression.…”

Section: Dovepresssupporting

confidence: 89%

Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

Zhang¹,

Yan²,

Ban³

et al. 2021

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Background There is an urgent need for the development of effective noninvasive biomarkers for early pancreatic cancer diagnosis. MicroRNAs (miRNAs) are promising candidates that can be identified in peripheral blood and can act as “liquid biopsy” biomarkers. miR-483-3p is overexpressed in the tumor tissue of pancreatic duct adenocarcinoma, but its potential as noninvasive biomarker remains unknown. Methods We conducted locked nucleic acid in situ hybridization (LNA-ISH) for miR-483-3p in archival tissues of 107 patients with PDAC. We also used immunohistochemistry to evaluate SMAD4 expression, the putative miR-483-3p target gene. miR-483-3p expression level was also assessed using quantitative real-time PCR (qRT-PCR) in serum and serum exosome samples from 63 patients with PDAC and 22 healthy individuals. Results LNA-ISH showed that miR-483-3p was overexpressed in PDAC and PanIN tissues compared to normal pancreatic duct cells. miR-483-3p expression levels correlated with increases in PanIN lesion grade. miR-483-3p expression negatively correlated with Smad4 expression (γ=−0.770, p<0.0001) in PDAC and PanIN tissues. Circulating miR-483-3p levels were significantly elevated in the serum and serum exosomes of PDAC patients compared to healthy controls (p<0.0001 and p<0.01, respectively). Specifically, serum miR-483-3p levels were able to distinguish patients with early stage (≤2cm) PDAC from healthy controls with an AUC of 0.83 [95% CI, 0.70–0.96]. Higher serum exosomal miR-483-3p levels predicted worse survival in PDAC patients and serum exosomal miR-483-3p also proved to be an independent prognostic factor for PDAC (hazard ratio = 3.307; 95% CI=1.104 to 9.903; p=0.033). In vitro studies also showed that miR-483-3p promoted pancreatic cancer cell migration and invasion. Conclusion miR-483-3p overexpression occurs early in PDAC development and is present in premalignant PanIN lesions. Serum miR-483-3p may act as an early PDAC diagnostic biomarker and serum exosomal miR-483-3p may be a PDAC prognostic biomarker.

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Section: Dovepresssupporting

confidence: 89%

Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

Zhang¹,

Yan²,

Ban³

et al. 2021

OTT

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“…Besides, TMB has emerged as a promising novel biomarker in predicting the prognosis and immune response in various cancers ( 29 ). We discovered that high mutation rates were associated with genes ( KARS and TP53 ) ( 30 ), which were mostly related to cancer progress, tumor angiogenesis, and metastasis ( 31 – 33 ). TICS showed a modest negative relationship with the TMB score ( r = −0.28, p < 0.05).…”

Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating Immune Cell Signature Predicts the Prognosis and Chemosensitivity of Patients With Pancreatic Ductal Adenocarcinoma

et al. 2020

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Tumor-infiltrating immune cells might add a predictive value for the prognostic stratification of patients with pancreatic ductal adenocarcinoma (PDAC) and chemotherapy response. We aimed to develop a prognostic model based on the tumorinfiltrating immune cell signature to improve the prediction of survival and chemotherapy benefits of patients with PDAC. Methods: The abundance of tumor-infiltrating immune cells for 661 patients with PDAC from four different cohorts with survival data was collected in the training cohorts. Cox regression analysis and meta-analysis of immune cells were conducted to generate the tumor immune cell score (TICS) for prognostic stratification. Other two independent cohorts including 188 patients were then used to validate the model. Those patients who underwent chemotherapy were used to further analyze the value of TICS for predicting the chemotherapy response. Furthermore, the difference in the somatic mutations and immune-related molecules between the TICS subgroups was analyzed. Results: 6 out of 28 immune cells were found to be significantly associated with PDAC prognosis in the training cohorts (all P < 0.05). The developed TICS could significantly predict the PDAC survival and chemotherapy benefit both in the training and the external validation cohorts (log-rank test, P < 0.05). Significant differences were found in different TICS subgroups in terms of the immune characteristics, checkpoint genes, and tumor mutational burden. Functional and pathway analyses further proved that the TICS was significantly related to the tumor immunity response in patients with PDAC. Conclusion: TICS might be used to predict PDAC patients with a better survival and greater chemotherapy benefit.

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“…181 Mutations in the genes that encode Smad transcription factor proteins, which are key mediators of TGF-β signalling, can promote TGF-β-mediated EMT. 182,183 Furthermore, driver mutations in the APC, CTNNB1 and NOTCH1 genes, and other components of the WNT and Notch signalling pathways, contribute to EMT in various cancers. [184][185][186] Miscellaneous genes As a consequence of mutation, genes that are not directly related to the regulation of cell movement can sometimes acquire new functions and thus promote cancer cell migration and invasion.…”

Section: Emt Regulatorsmentioning

confidence: 99%

Mutational drivers of cancer cell migration and invasion

et al. 2020

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Genomic instability and mutations underlie the hallmarks of cancer—genetic alterations determine cancer cell fate by affecting cell proliferation, apoptosis and immune response, and increasing data show that mutations are involved in metastasis, a crucial event in cancer progression and a life-threatening problem in cancer patients. Invasion is the first step in the metastatic cascade, when tumour cells acquire the ability to move, penetrate into the surrounding tissue and enter lymphatic and blood vessels in order to disseminate. A role for genetic alterations in invasion is not universally accepted, with sceptics arguing that cellular motility is related only to external factors such as hypoxia, chemoattractants and the rigidity of the extracellular matrix. However, increasing evidence shows that mutations might trigger and accelerate the migration and invasion of different types of cancer cells. In this review, we summarise data from published literature on the effect of chromosomal instability and genetic mutations on cancer cell migration and invasion.

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SMAD4 Y353C promotes the progression of PDAC

Cited by 19 publications

References 52 publications

Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

Tumor-Infiltrating Immune Cell Signature Predicts the Prognosis and Chemosensitivity of Patients With Pancreatic Ductal Adenocarcinoma

Mutational drivers of cancer cell migration and invasion

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