Browsing by Author "Tang, Chih-Hsin"

Now showing 1 - 6 of 6

Amphiregulin promotes cisplatin chemoresistance by upregulating ABCB1 expression in human chondrosarcoma
(2020-05-31)
Huang, Yu-Wen
;
Lin, Chih-Yang
;
Tsai, Hsiao-Chi
;
Fong, Yi-Chin
;
Han, Chien-Kuo
Chondrosarcomas are well known for their resistance to chemotherapeutic agents, including cisplatin, which is commonly used in chondrosarcomas. Amphiregulin (AR), a ligand of epidermal growth factor receptor (EGFR), plays an important role in drug resistance. We therefore sought to determine the role of AR in cisplatin chemoresistance. We found that AR inhibits cisplatin-induced cell apoptosis and promotes ATP-binding cassette subfamily B member 1 (ABCB1) expression, while knockdown of ABCB1 by small interfering RNA (siRNA) reverses these effects. High phosphoinositide 3-kinase (PI3K), Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) phosphorylation levels were observed in cisplatin-resistant cells. Pretreating chondrosarcoma cells with PI3K, Akt and NF-kappa B inhibitors or transfecting the cells with p85, Akt and p65 siRNAs potentiated cisplatin-induced cytotoxicity. In a mouse xenograft model, knockdown of AR expression in chondrosarcoma cells increased the cytotoxic effects of cisplatin and also decreased tumor volume and weight. These results indicate that AR upregulates ABCB1 expression through the PI3K/Akt/NF-kappa B signaling pathway and thus contributes to cisplatin resistance in chondrosarcoma.
CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma
(2018-09-20)
Tzeng, Huey-En
;
Tang, Chih-Hsin
;
Wu, Sz-Hua
;
Chen, Hsien-Te
;
Fong, Yi-Chin
Chondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NE-KB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NE-KB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.
Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin alpha 4 beta 1 system
(2018-01-01)
Chang, An-Chen
;
Chen, Po-Chun
;
Lin, Yu-Feng
;
Su, Chen-Ming
;
Liu, Ju-Fang
Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin alpha 4 beta 1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin alpha 4 beta 1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin alpha 4 beta 1 serves as a ligand that captures VCAM-1(+) metastatic tumor cells adhering to osteoblasts. Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin alpha 4 beta 1 system. Osteoblast-derived WISP-1 is a promising target for the prevention and inhibition of PCa-bone interaction. (C) 2018 Elsevier B.V. All rights reserved.
Periostin promotes epithelial-mesenchymal transition via the MAPK/miR-381 axis in lung cancer
(2017-09-05)
Hu, Wei-Wei
;
Chen, Po-Chun
;
Chen, Jun-Ming
;
Wu, Yue-Ming
;
Liu, Po-Yi
Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a multifunctional cytokine that signals between the cell and the extracellular matrix. Periostin plays an important role in tumor development and is involved in carcinoma cell epithelial-mesenchymal transition (EMT), whereby mature epithelial cells undergo phenotypic morphological changes and become invasive, motile cells. Here, we discuss the molecular mechanisms involved in periostin-induced promotion of EMT in lung cancer cells. Online TCGA datasets demonstrate the prognostic relevance of periostin in lung cancer; a higher periostin level correlates with poor overall survival. Similarly, our IHC results show that high periostin expression is positively correlated with the EMT markers Snail and Twist, as well as stage of lung cancer. We found that recombinant periostin induces the EMT phenotype in lung cancer cells through the p38/ERK pathway, while pretreatment with chemical inhibitors prevented periostin-induced EMT induction. Moreover, we found that periostin regulates EMT by repressing microRNA-381 (miR-381) expression, which targets both Snail and Twist. Using the miR-381 mimic, we dramatically reversed periostin-induced Snail and Twist expression. Furthermore, periostin knockdown dramatically affected EMT markers and cell migration potential. The role of periostin in lung cancer progression is elucidated by the in vivo mouse model. Our findings indicate that changes in periostin expression in lung cancer may serve as a therapeutic target for the treatment of lung cancer metastasis.
Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells
(2019-04-01)
Tai, Huai-Ching
;
Lee, Tzong-Huei
;
Tang, Chih-Hsin
;
Chen, Lei-Po
;
Chen, Wei-Cheng
Lymphangiogenesis is an important biological process associated with cancer metastasis. The development of new drugs that block lymphangiogenesis represents a promising therapeutic strategy. Marine fungus-derived compound phomaketide A, isolated from the fermented broth of Phoma sp. NTOU4195, has been reported to exhibit anti-angiogenic and anti-inflammatory effects. However, its anti-lymphangiogenic activity has not been clarified to date. In this study, we showed that phomaketide A inhibited cell growth, migration, and tube formation of lymphatic endothelial cells (LECs) without an evidence of cytotoxicity. Mechanistic investigations revealed that phomaketide A reduced LECs-induced lymphangiogenesis via vascular endothelial growth factor receptor-3 (VEGFR-3), protein kinase C (PKC), and endothelial nitric oxide synthase (eNOS) signalings. Furthermore, human proteome array analysis indicated that phomaketide A significantly enhanced the protein levels of various protease inhibitors, including cystatin A, serpin B6, tissue factor pathway inhibitor (TFPI), and tissue inhibitor matrix metalloproteinase 1 (TIMP-1). Importantly, phomaketide A impeded tumor growth and lymphangiogenesis by decreasing the expression of LYVE-1, a specific marker for lymphatic vessels, in tumor xenograft animal model. These results suggest that phomaketide A may impair lymphangiogenesis by suppressing VEGFR-3, PKC, and eNOS signaling cascades, while simultaneously activating protease inhibitors in human LECs. We document for the first time that phomaketide A inhibits lymphangiogenesis both in vitro and in vivo, which suggests that this natural product could potentially treat cancer metastasis.
Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells
(2018-09-01)
Liu, Ju-Fang
;
Lee, Chiang-Wen
;
Tsai, Ming-Horng
;
Tang, Chih-Hsin
;
Chen, Po-Chun
Thrombospondin (TSP)-2, a matricellular glycoprotein of the TSP family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion, and extracellular matrix (ECM) modeling. The clinical relevance of TSP-2 has been explored in many different cancers. TSP-2 expression levels vary between different cancer types, and their role in tumor progression remains controversial. Although previous studies have reported higher serum TSP-2 levels in patients with non-small cell lung cancer, the role of TSP-2 in lung cancer progression remains to be addressed. A total of 585 lung adenocarcinoma datasets, including mRNA sequencing and clinical data, were retrieved from The Cancer Genome Atlas (TCGA). Forty paired adjacent normal tissues and lung tumor tissue datasets were used to examine TSP-2 expression levels. Tumor microarray were performed with immunohistochemical staining to examine TSP-2 expression in lung cancer patients. Transwell migration assay, quantitative real-time PCR and Western blot were used to investigate molecular mechanism of TSP-2 in lung cancer cell. TSP-2 promotes matrix metalloproteinase-13 (MMP-13) expression, cell migration, and cell invasion by mediating integrin alpha v beta 3/FAK/Akt/NF-kappa B signal transduction. Using TSP-2 knockdown stable cell lines, we found that TSP-2 knockdown reduces MMP-13 expression and cell mobility. When we manipulated the tumor tissue microarray and TCGA datasets to investigate the clinical relevance of TSP-2, we found high TSP-2 expression levels in lung cancer specimens. The present study demonstrates that TSP-2 regulates cell mobility through MMP-13 expression in lung cancer cells. In addition, TSP-2 expression was associated with MMP-13 expression and poor prognosis in lung cancer. TSP-2 may therefore be a promising novel target for lung cancer treatment.