PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer

Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of this disease, particularly in breast cancers characterized by high aggressiveness and metastatic potential. In order to identify and characterize genes with novel functions as regulators of tumor cell migration and invasion, we performed a genetic loss-of-function screen using a shRNA library directed against the Ubiquitin Proteasome System (UPS) in a highly invasive breast cancer derived cell line. Among the candidates, we validated HERC1 as a gene regulating cell migration and invasion. Furthermore, using animal models, our results indicated that HERC1 silencing affects primary tumor growth and lung colonization. Finally, we conducted an in-silico analysis using publicly available protein expression data and observed an inverse correlation between HERC1 expression levels and breast cancer patients overall survival. Altogether, our findings demonstrate that HERC1 might represent a novel therapeutic target for the development or improvement of breast cancer treatment.

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HERC1 Regulates Breast Cancer Cells Migration and Invasion

Cancers ◽

10.3390/cancers13061309 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1309

Author(s):

Fabiana Alejandra Rossi ◽

Ezequiel Hernán Calvo Roitberg ◽

Juliana Haydeé Enriqué Steinberg ◽

Molishree Umesh Joshi ◽

Joaquín Maximiliano Espinosa ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Cell ◽

Inverse Correlation ◽

Migration And Invasion ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Loss Of Function ◽

Cell Migration And Invasion ◽

Tumor Cell Migration

Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of this disease, particularly in breast cancers characterized by high aggressiveness and metastatic potential. To identify and characterize genes with novel functions as regulators of tumor cell migration and invasion, we performed a genetic loss-of-function screen using a shRNA library directed against the Ubiquitin Proteasome System (UPS) in a highly invasive breast cancer derived cell line. Among the candidates, we validated HERC1 as a gene regulating cell migration and invasion. Furthermore, using animal models, our results indicate that HERC1 silencing affects primary tumor growth and lung colonization. Finally, we conducted an in silico analysis using publicly available protein expression data and observed an inverse correlation between HERC1 expression levels and breast cancer patients’ overall survival. Altogether, our findings demonstrate that HERC1 might represent a novel therapeutic target for the development or improvement of breast cancer treatment.

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USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Oncogenesis ◽

10.1038/s41389-021-00318-x ◽

2021 ◽

Vol 10 (3) ◽

Author(s):

Fabiana Alejandra Rossi ◽

Juliana Haydeé Enriqué Steinberg ◽

Ezequiel Hernán Calvo Roitberg ◽

Molishree Umesh Joshi ◽

Ahwan Pandey ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Cell ◽

Therapeutic Target ◽

Migration And Invasion ◽

Invasive Potential ◽

Cell Migration And Invasion ◽

Tumor Cell Migration ◽

Ubiquitination Pathway

AbstractTumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

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USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

10.1101/2020.07.01.181883 ◽

2020 ◽

Author(s):

Fabiana A Rossi ◽

Juliana H Enriqué Steinberg ◽

Ezequiel H Calvo Roitberg ◽

Molishree Joshi ◽

Ahwan Pandey ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Cell ◽

Therapeutic Target ◽

Migration And Invasion ◽

Invasive Potential ◽

Cell Migration And Invasion ◽

Tumor Cell Migration ◽

Ubiquitination Pathway

ABSTRACTTumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

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