Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells

Završnik, Janja; Butinar, Miha; Prebanda, Mojca Trstenjak; Krajnc, Aleksander; Vidmar, Robert; Fonović, Marko; Grubb, Anders; Türk, Vito; Turk, Boris; Vasiljeva, Olga

doi:10.18632/oncotarget.17379

Cited by 24 publications

(12 citation statements)

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“…CTSZ belongs to the cathepsin family of lysosomal hydrolases that contribute to the turnover of intra cellular proteins and the degradation of extracellular matrix [ 25 ]. Interestingly, several of the tumor-promoting functions of CTSZ were not dependent on its described catalytic activity [ 26 ]. Several proteases have been shown to mediate adhesion and migration of cells through interaction with integrins [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several proteases have been shown to mediate adhesion and migration of cells through interaction with integrins [ 27 ]. CTSZ contains an Arg-Gly-Asp (RGD) motif allows it to interact with integrins [ 26 , 28 ]. RGD is a protein sequence vital to the binding of proteins to cell surface [ 29 ], which mediates cell adhesive properties, and this region interacts with the integrin αvb3 [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

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Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation

et al. 2017

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Gastric cancer (GC) is a globally occurring malignancy that is characterized by a high mortality rate due to a high tendency to metastasize and poor prognoses. Sorcin, as known as SRI, a soluble resistance-related calcium-binding protein, plays a significant role in multidrug resistance. Sorcin is related to the migration and invasion of cancer cells. However, the mechanism remains unclear. Here, we used immunohistochemistry to confirm that the expression of sorcin in cancer tissues is higher than that in the adjacent normal tissues. The wound healing and transwell results indicate that sorcin can induce migration and invasion of GC cells. To explore the role of sorcin in GC metastasis, isobaric tags for relative and absolutely quantitation (iTRAQ) were used to examine cells with and without sorcin knockdown to identify the differentially expressed proteins (DEPs). The results were evaluated via RT-PCR and western blot to confirm the ITRAQ data. Inhibition of sorcin expression can down- regulate the expression of CTSZ, MMP2, MMP9 and p-STAT3 followed by suppression of tumor growth and metastasis. Together, we concluded that sorcin has a oncogenic activity via inducing tumor growth and metastasis, leading to development of therapeutic treatments for GC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation

et al. 2017

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“…The first study revealed that genetic ablation of cystatin C, major extracellular cathepsin inhibitor, in the pancreatic neurocrine tumor model (Rip-Tag2) resulted in an increased size of islet cell carcinomas and angiogenic islets, which was linked to deregulated cathepsin S activity leading to increased endostatin generation [91]. The other two studies available included genetic ablation of stefin B, the major intracellular cathepsin inhibitor [131], and of cystatin C [132], in the mammary gland PyMT mouse model. However, contrary to all expectation, tumors were smaller in both inhibitor knock-out models despite the increased cathepsin activity in the tumors.…”

Section: Ecm Proteolysis and The Cathepsinsmentioning

confidence: 99%

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

Vidak

Javoršek

Vizovišek

et al. 2019

Cells

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: For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.

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“…Twenty visual fields per tumor section (20x magnification) in non-necrotic areas were quantified using ImageJ software (https:// imagej.nih.gov/ij/ ) and the Immunohistochemistry Image Analysis Toolbox. 6 , 38 , 39 …”

Section: Methodsmentioning

confidence: 99%

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Breznik

Limback

Porčnik

et al. 2018

Radiology and Oncology

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BackgroundGlioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.Materials and methodsGene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.ResultsHighest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.ConclusionsThe presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

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Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells

Cited by 24 publications

References 88 publications

Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation

Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

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