c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target

Refaat, Tamer; Donnelly, Eric D.; Sachdev, Sean; Parimi, Vamsi; Achy, Samar El; Dalal, Prarthana; Farouk, Mohamed; Berg, Natasha; Helenowski, Irene; Gross, Jeffrey P.; Lurain, John R.; Strauss, Jonathan B.; Woloschak, Gayle E.; Wei, Jian Jun; Small, William

doi:10.1097/coc.0000000000000203

Cited by 23 publications

(7 citation statements)

References 36 publications

(37 reference statements)

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“…Serving as an oncogene, c-Met activates multiple pathways and amplifies the transduction cascade to further mediate tumor cell behaviors [27]. C-Met is also considered as predictive marker of prognosis of tumor patients [28–30]. In this study, c-Met was upregulated in OS tissues and cell lines.…”

Section: Discussionmentioning

confidence: 81%

MicroRNA-449b-5p Suppresses Proliferation, Migration, and Invasion of Osteosarcoma by Targeting c-Met

Wang

et al. 2019

Med Sci Monit

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Background The aim of this study was to clarify the biological function of microRNA-449b-5p in the progression of osteosarcoma (OS) and to define the underlying mechanism. Material/Methods Relative levels of microRNA-449b-5p in OS tissues and cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between microRNA-449b-5p level and pathological characteristics of OS patients was analyzed by chi-square test. Kaplan-Meier analysis was used for survival analysis of OS patients based on their expression level of microRNA-449b-5p. Regulatory effects of microRNA-449b-5p on cellular behaviors of OS cells were evaluated by cell counting kit-8 (CCK-8) and Transwell assay. The binding relationship between microRNA-449b-5p and c-Met was verified through dual-luciferase reporter gene assay, and their interaction in OS progression was further examined through a series of rescue experiments. Results MicroRNA-449b-5p was expressed at low levels in OS. Lower levels of microRNA-449b-5p were seen in OS tissues with worse tumor grade or histological differentiation. OS patients with low levels of microRNA-449b-5p had worse overall survival relative to those with high level of microRNA-449b-5p. Overexpression of microRNA-449b-5p markedly attenuated proliferative, migratory, and invasive abilities of OS cells. C-Met is the downstream target of microRNA-449b-5p, and its level was inhibited in OS cells overexpressing microRNA-449b-5p. Importantly, c-Met partially rescued the inhibitory effects of microRNA-449b-5p on behavior of OS cells. Conclusions MicroRNA-449b-5p is downregulated in OS, which alleviates the malignant progression of OS by targeting c-Met.

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Section: Discussionmentioning

confidence: 81%

MicroRNA-449b-5p Suppresses Proliferation, Migration, and Invasion of Osteosarcoma by Targeting c-Met

Wang

et al. 2019

Med Sci Monit

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“…RASGRP appears as a miR-34c-3p validated target in the DIANA database, while PDGFB was not validated in the databases consulted. The genes participating in the six cell-signaling pathways potentially regulated by 5p and 3p strands of miR-34 family members are overexpressed in cervical cancer [46,47,48,49,50,51,52,53]. The genes encoding VGEF, RRAS2, PRKCB, RASGRP, and PDGFB involved in the six cell-signaling pathways are not currently reported in cervical cancer; however, they were reported as overexpressed in other carcinomas [54,55,56,57,58], suggesting their participation in carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells

Córdova-Rivas

Fraire-Soto

Torres

et al. 2019

IJMS

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The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand’s expression and function is studied in cervical cancer. The 3p strand’s function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer.

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Section: Introductionmentioning

confidence: 99%

“…10 Previous studies also found that the physiological function of HGF/c-Met axis revolves around cell motility and invasive growth, and displayed a higher activity in many cancers. [11][12][13][14] PHA-665752 is a potent, selective and ATP competitive c-Met inhibitor. As early as in 2003, Christensen et al 15 have found that PHA-665752 could inhibit the c-metdependent phenotype in vitro and exhibit anti-tumor activity in vivo.…”

Section: Introductionmentioning

confidence: 99%

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Chen¹,

Wu²,

Huang³

et al. 2021

OTT

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Introduction Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. Methods In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC 50 value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. Results Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. Conclusion Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.

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c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target

Cited by 23 publications

References 36 publications

MicroRNA-449b-5p Suppresses Proliferation, Migration, and Invasion of Osteosarcoma by Targeting c-Met

MicroRNA-449b-5p Suppresses Proliferation, Migration, and Invasion of Osteosarcoma by Targeting c-Met

5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

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