PRSS3/mesotrypsin in prostate cancer progression: implications for translational medicine

Radisky, Evette S.

doi:10.1038/aja.2013.14

Cited by 11 publications

(14 citation statements)

References 14 publications

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“…Therefore, our data highlight the importance of circ-ADAM9/ miR-217 axis in regulating PRSS3 and also provide novel insights into PC tumourigenesis. PRSS3 is an atypical subtype of trypsinogen that has been implicated to be aberrantly expressed in different tumours, including PC [10,20,21]. However, little is known about the underlying mechanisms of PRSS3 dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression

Xing

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Pancreatic cancer (PC) is a highly lethal human cancer. We previously found that Serine protease 3 (PRSS3), as an oncogene, is significantly upregulated in PC. In this study, we aimed to investigate the potential mechanism of PRSS3 dysregulation in PC. In this research, low miR-217 and high circ-ADAM9 expression were found in PC tissues and cell lines, which was closely associated with advanced clinical stage and lymph node metastasis. Patients with low miR-217 or high circ-ADAM9 expression had shorter survival time than those with high miR-217 or low circ-ADAM9 expression. Functionally, manipulation of miR-217 and circ-ADAM9 expression showed opposite effects on cell proliferation, migration and invasion. Stepwise mechanism studies indicated that circ-ADAM9 alleviated the inhibitory effect of miR-217 on PRSS3 by directly sponging miR-217 to increase the expression level of PRSS3, resulting in the activation of ERK/VEGF signalling pathway. In vivo, circ-ADAM9 silencing or miR-217 overexpression evidently retarded the growth of tumour, and the combination of them exhibited an additive inhibitory effect on tumourigenicity. Briefly, the ceRNA regulatory network of circ-ADAM9/ miR-217/PRSS3 plays a pivotal role in PC progression by the regulation of ERK/VEGF signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression

Xing

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…We previously have studied the interaction of mesotrypsin with APPI in detail, finding it to be a good substrate (15). Of the remaining 10 Kunitz domains, we were primarily interested in pursuing those representing potentially relevant substrates or inhibitors of mesotrypsin in the context of prostate cancer, because we have recently identified mesotrypsin as a driver of metastatic progression and a potential therapeutic target in prostate cancer (10,11). The majority of the Kunitz domain-containing proteins were seen to be expressed at moderate or high levels in prostate cancer cell lines; however, WFIKKN1 was not expressed in prostate tissue, tumors, or tumor cell lines and was not considered further in our study.…”

Section: Resultsmentioning

confidence: 99%

“…These alternative isoforms, trypsinogens 4 and 5, do not possess classic signal sequences, and the mechanisms by which they are trafficked and activated are not yet fully elucidated, but functional studies provide evidence for significant roles for active mesotrypsin in keratinocyte differentiation and skin desquamation (6,7). PRSS3 transcripts, primarily encoding trypsinogen 4, are also expressed in many epithelial cells and cancers, and functional studies likewise provide evidence for extracellular roles for active mesotrypsin in tumor progression of breast (8), pancreatic (9), and prostate cancers (10,11). An unusual feature of mesotrypsin is its extreme resistance to endogenous proteinaceous trypsin inhibitors (1,12,13) and its ability to digest some of these inhibitors as substrates (6,14,15).…”

Section: Mesotrypsin Is An Isoform Of Trypsin That Is Uniquely Resistmentioning

confidence: 99%

Sequence and Conformational Specificity in Substrate Recognition

Pendlebury

Wang

Henin

et al. 2014

Journal of Biological Chemistry

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Background: Mesotrypsin targets protease inhibitors as substrates; substrate recognition depends on sequence and conformational motifs. Results: Mesotrypsin cleaves three human Kunitz domains as specific substrates, but other similarly shaped substrates are cleaved less efficiently. Conclusion: Substrate conformation aids recognition by mesotrypsin but is not sufficient for efficient cleavage. Significance: Mesotrypsin cleavage of human Kunitz domains may contribute to cancer progression.

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“…Other than PRSS1 and PRSS2 as the major digestive enzymes in the pancreas, PRSS3 is a minor constituent trypsin isoform but physiologically critical due to its resistance to common trypsin inhibitors [13][14][15]. In addition to digestive activity, PRSS3 has long been implicated in the pathogenesis of several malignancies and is therefore a promising biomarker and potential therapeutic target for cancer [21][22][23][24][25][26][27][28][29][30][31]. However, the functional roles associated with the expression of PRSS3 in cancer development are debatable.…”

mentioning

confidence: 99%

“…But on the other hand, PRSS3 was suggested as a tumor suppressor gene due to epigenetic silencing [32][33][34][35][36]. Although the evidence supports the dual roles of proteases in carcinogenesis depending on cellular sources and cancer microenvironment [11-13, 21-23, 32, 33, 35], the underlying molecular basis of PRSS3 for its pro-and anti-tumorigenic roles shown in different cancer types, even reported in the same type of cancer, such as in esophageal adenocarcinoma [25,34], lung cancer [24,33] and liver cancer [28,35], remains elusive that caused many miscellaneous aliases to PRSS3 impact its potential target-therapeutic applications [4,12,13,22,27,35].…”

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confidence: 99%

Epigenetic Dysregulation of the Expression of PRSS3 Splice Variants Increases the Heterogeneity of Transcripts and Functionality in Human Hepatocellular Carcinoma

Lin¹,

Xu²,

Pang³

et al. 2021

Preprint

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Background Hepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive heterogeneity. Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies including HCC. However, paradoxical effects of PPRSS3 on carcinogenesis impede the utilization of its biomarker potential. We hereby systematically dissected the expression of four known splice variants of PRSS3 (PRSS3-SVs) and their functional relevance to HCC. Methods The expression and DNA methylation of PRSS3 transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and were validated using qPCR-based assays. Functional assays were performed on gain- and loss-of-function cell models, in which PRSS3 transcript constructs were separately transfected after PRSS3 expression was knocked out by CRISPR-Cas9 editing. Results PRSS3 expression was differentially decreased in HCC cell lines and tissues attributable to aberrant expression of PRSS3-SVs towards bipolarity, in which PRSS3-V2 and then -V1 were dominantly expressed whereas PRSS3-V3 and -V4 were rarely or minimally expressed. The expression of PRSS3-V2 or -V1 was reversely associated with site-specific CpG methylation and was distinct between lowly-expressed PRSS3-SVs with hypermethylation (mPRSS3Low) and highly-expressed PRSS3-SVs with hypomethylation (umPRSS3High). Function analysis revealed that PRSS3-V2 exhibited oncogenic functions distinct from a tumor-suppressive role of ectopic PRSS3-V1 or -V3, or PRSS3-V4 with inhibitory effects in PRSS3 knockout HCC cells. Clinically, aberrant expression of PRSS3-SVs was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of PRSS3-V2 was seen in early HCC and was associated with favorable patient outcome. Conclusions Aberrant expression of divergent PRSS3-SVs disrupted by CpG methylation may integrate the effects of oncogenic PRSS3-V2 and tumor-suppressive PRSS3-V1, resulting in the molecular diversity and functional plasticity of HCC. Dysregulated expression of PRSS3-V2 by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.

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PRSS3/mesotrypsin in prostate cancer progression: implications for translational medicine

Cited by 11 publications

References 14 publications

Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression

Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression

Sequence and Conformational Specificity in Substrate Recognition

Epigenetic Dysregulation of the Expression of PRSS3 Splice Variants Increases the Heterogeneity of Transcripts and Functionality in Human Hepatocellular Carcinoma

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