Differential roles of protease isoforms in the tumor microenvironment

Liyanage, Chamikara; Fernando, Achala; Batra, Jyotsna

doi:10.1007/s10555-019-09816-2

Cited by 13 publications

(11 citation statements)

References 230 publications

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“…Notably, these included events that have previously been identified: for example, BTG3 , which has been found to be differentially spliced in lung cancers ( Chen et al, 2013 ), appeared to be most highly expressed in T-cells and NK cells, and inclusion of exon 4 was significantly higher in CD4+ T-cells than other cell types ( Supplementary Figure 18A ). Similarly, several CTSB splice variants, including one lacking exon 2, have been shown to be differentially expressed in cancer ( Liyanage et al, 2019 ), and we found evidence in our dataset that CD14+ monocytes had significantly more expression of exon 2 than other cell types ( Supplementary Figure 18B ). Our results thus indicate that DLP-scRNAseq can be used to study AS transcripts enriched in comparisons of cell types.…”

Section: Resultssupporting

confidence: 67%

A Scalable Strand-Specific Protocol Enabling Full-Length Total RNA Sequencing From Single Cells

et al. 2021

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RNA sequencing (RNAseq) has been widely used to generate bulk gene expression measurements collected from pools of cells. Only relatively recently have single-cell RNAseq (scRNAseq) methods provided opportunities for gene expression analyses at the single-cell level, allowing researchers to study heterogeneous mixtures of cells at unprecedented resolution. Tumors tend to be composed of heterogeneous cellular mixtures and are frequently the subjects of such analyses. Extensive method developments have led to several protocols for scRNAseq but, owing to the small amounts of RNA in single cells, technical constraints have required compromises. For example, the majority of scRNAseq methods are limited to sequencing only the 3′ or 5′ termini of transcripts. Other protocols that facilitate full-length transcript profiling tend to capture only polyadenylated mRNAs and are generally limited to processing only 96 cells at a time. Here, we address these limitations and present a novel protocol that allows for the high-throughput sequencing of full-length, total RNA at single-cell resolution. We demonstrate that our method produced strand-specific sequencing data for both polyadenylated and non-polyadenylated transcripts, enabled the profiling of transcript regions beyond only transcript termini, and yielded data rich enough to allow identification of cell types from heterogeneous biological samples.

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Section: Resultssupporting

confidence: 67%

A Scalable Strand-Specific Protocol Enabling Full-Length Total RNA Sequencing From Single Cells

et al. 2021

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“…Thus, this isoform 4 may act distinctly compared to full-length isoforms by various mechanisms. Recent studies have elucidated that cancer-associated AS of transcription factors generates isoforms with altered activity, opposite transcription or antagonistic functions that severely impact tumor initiation and progression [ 3 ]. As Belluti et al summarized, the lack of binding domains in transcription factors can show opposite functions in cancer progression [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…Apart from the contribution to the greater diversity of the proteome, AS leads to every hallmark of cancer progression [ 2 ]. Recent study findings predict that the vast heterogeneity of human cancers may be a result of the distinct roles of protease isoforms resulting from AS [ 3 ]. AS has been reported to modify the network of protein interactions in a disruptive, non-regulated manner, thus disrupting normal cell function via mediating cancer driven pathways [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Fernando

Liyanage

Moradi

et al. 2021

Genes

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Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.

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“…The pharmacological properties of protease inhibitors have been characterized and studied for decades in different biological models for therapeutic applications [8,9]. Their effectiveness may be due to direct inhibition of extracellular matrix (ECM) proteolysis or indirect inhibition of proteolytic cascade activation, thus preventing the spread of tumor cells, ECM degradation, and inhibition of tumor progression [8].…”

Section: Discussionmentioning

confidence: 99%

Differences in the Inhibitory Specificity Distinguish the Efficacy of Plant Protease Inhibitors on Mouse Fibrosarcoma

Bonturi

Nakahata

et al. 2021

Plants

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Metastasis, the primary cause of death from malignant tumors, is facilitated by multiple protease-mediated processes. Thus, effort has been invested in the development of protease inhibitors to prevent metastasis. Here, we investigated the effects of protease inhibitors including the recombinant inhibitors rBbKI (serine protease inhibitor) and rBbCI (serine and cysteine inhibitor) derived from native inhibitors identified in Bauhinia bauhinioides seeds, and EcTI (serine and metalloprotease inhibitor) isolated from the seeds of Enterolobium contortisiliquum on the mouse fibrosarcoma model (lineage L929). rBbKI inhibited 80% of cell viability of L929 cells after 48 h, while EcTI showed similar efficacy after 72 h. Both inhibitors acted in a dose and time-dependent manner. Conversely, rBbCI did not significantly affect the viability of L929 cells. Confocal microscopy revealed the binding of rBbKI and EcTI to the L929 cell surface. rBbKI inhibited approximately 63% of L929 adhesion to fibronectin, in contrast with EcTI and rBbCI, which did not significantly interfere with adhesion. None of the inhibitors interfered with the L929 cell cycle phases. The synthetic peptide RPGLPVRFESPL-NH2, based on the BbKI reactive site, inhibited 45% of the cellular viability of L929, becoming a promising protease inhibitor due to its ease of synthesis.

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Differential roles of protease isoforms in the tumor microenvironment

Cited by 13 publications

References 230 publications

A Scalable Strand-Specific Protocol Enabling Full-Length Total RNA Sequencing From Single Cells

A Scalable Strand-Specific Protocol Enabling Full-Length Total RNA Sequencing From Single Cells

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Differences in the Inhibitory Specificity Distinguish the Efficacy of Plant Protease Inhibitors on Mouse Fibrosarcoma

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