1.Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo
Ching-Ling LIN ; Ming-Lin TSAI ; Yu-hsin CHEN ; Wei-Ni LIU ; Chun-Yu LIN ; Kai-Wen HSU ; Chien-Yu HUANG ; Yu-Jia CHANG ; Po-Li WEI ; Shu-Huey CHEN ; Li-Chi HUANG ; Chia-Hwa LEE
Biomolecules & Therapeutics 2021;29(5):551-561
Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.
2.Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo
Ching-Ling LIN ; Ming-Lin TSAI ; Yu-hsin CHEN ; Wei-Ni LIU ; Chun-Yu LIN ; Kai-Wen HSU ; Chien-Yu HUANG ; Yu-Jia CHANG ; Po-Li WEI ; Shu-Huey CHEN ; Li-Chi HUANG ; Chia-Hwa LEE
Biomolecules & Therapeutics 2021;29(5):551-561
Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.
3.The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells.
Chun Yu LIU ; Tzu Ting HUANG ; Pei Yi CHU ; Chun Teng HUANG ; Chia Han LEE ; Wan Lun WANG ; Ka Yi LAU ; Wen Chun TSAI ; Tzu I CHAO ; Jung Chen SU ; Ming Huang CHEN ; Chung Wai SHIAU ; Ling Ming TSENG ; Kuen Feng CHEN
Experimental & Molecular Medicine 2017;49(8):e366-
Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.
Apoptosis*
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Breast Neoplasms
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Disease-Free Survival
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Humans
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Protein-Tyrosine Kinases*
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RNA, Small Interfering
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Triple Negative Breast Neoplasms*
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Tyrosine*
4.Determining the risk factors associated with the development of Clostridium difficile infection in patients with hematological diseases
Yu Ling LEE-TSAI ; Rodrigo LUNA-SANTIAGO ; Roberta DEMICHELIS-GÓMEZ ; Alfredo PONCE-DE-LEÓN ; Eric OCHOA-HEIN ; Karla María TAMEZ-TORRES ; María T BOURLON ; Christianne BOURLON
Blood Research 2019;54(2):120-124
BACKGROUND: Clostridium difficile infection (CDI) is a nosocomial condition prevalent in patients with hematological disorders. We aimed to identify the risk factors associated with the development of CDI and assess the mortality rate at 15 and 30 days among hematologic patients admitted to a tertiary care center. METHODS: We conducted a retrospective case-control study from January 2010 to December 2015. Forty-two patients with hematologic malignancy and CDI, and 84 with hematologic disease and without history of CDI were included in the case and control groups, respectively. RESULTS: Univariate analysis revealed that episodes of febrile eutropenia [odds ratio (OR), 5.5; 95% confidence interval (CI), 2.3–12.9; P<0.001], admission to intensive care unit (OR, 3.8; 95% CI, 1.4–10.2; P=0.009), gastrointestinal surgery (OR, 1.2; 95% CI, 1.1–1.4; P<0.001), use of therapeutic (OR, 6.4; 95% CI, 2.5–15.9; P<0.001) and prophylactic antibiotics (OR, 4.2; 95% CI, 1.6–10.7; P=0.003) in the last 3 months, and >1 hospitalization (OR, 5.6; 95% CI, 2.5–12.6; P<0.001) were significant risk factors. Multivariate analysis showed that use of therapeutic antibiotics in the last 3 months (OR, 6.3; 95% CI, 2.1–18.8; P=0.001) and >1 hospitalization (OR, 4.3; 95% CI, 1.7–11.0; P=0.002) were independent risk factors. Three (7.1%) and 6 (14.2%) case patients died at 15 and 30 days, respectively. CONCLUSION: The risk factors for developing CDI were exposure to therapeutic antibiotics and previous hospitalization. Hematological patients who developed CDI had higher early mortality rates, suggesting that new approaches for prevention and treatment are needed.
Anti-Bacterial Agents
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Case-Control Studies
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Clostridium difficile
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Clostridium
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Hematologic Diseases
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Hematologic Neoplasms
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Hospitalization
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Humans
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Intensive Care Units
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Mortality
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Multivariate Analysis
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Retrospective Studies
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Risk Factors
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Tertiary Care Centers