Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma

Meng, Jie; Sun, Bei; Zhao, Xiulan; Zhang, Danfang; Zhao, Xiao‐Fan; Gu, Qing; Dong, Xueyi; Zhao, Nan; Pei-mei, Liu; Liu, Yanrong

doi:10.1158/1535-7163.mct-13-1060

Cited by 57 publications

(44 citation statements)

References 41 publications

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“…Since our studies show that there is Ͼ75% HeLa cell growth inhibition with 4 g/ml of doxycycline treatment, the results seen with the higher doxycycline concentrations (5 and 10 g/ml) used by Meng et al (49) suggest a possible doxycycline-induced toxic effect on hepatic tumor cells. Our RNA-seq data from the parental HeLa cells have further indicated very low expression of cadherins and MMPs and only modestly decreased expression in doxycycline-treated cells (data not shown).…”

Section: Discussionsupporting

confidence: 49%

“…Doxycycline treatment has been shown to inhibit hepatic tumor cell growth through inhibition of epithelial-to-mesenchymal transition (EMT) and by enhanced expression of E-cadherin and reduced expression of N-cadherin, vimentin, twist, and snail (49). Since our studies show that there is Ͼ75% HeLa cell growth inhibition with 4 g/ml of doxycycline treatment, the results seen with the higher doxycycline concentrations (5 and 10 g/ml) used by Meng et al (49) suggest a possible doxycycline-induced toxic effect on hepatic tumor cells.…”

Section: Discussionmentioning

confidence: 99%

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Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Soh

Venkatesan

Veena

et al. 2016

Molecular and Cellular Biology

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Cervical cancer is the second-most-common cancer responsible for cancer-related death in women around the world. The incidence is increasing, with 450,000 new cases diagnosed worldwide and 12,340 diagnosed in the United States annually (1, 2). It is the third leading cause of death from cancer in women 15 to 34 years of age and the fifth leading cause of death in women 35 to 54 years of age, representing about 2% of all cancers in women in the United States. The disease is frequently found in women who have had multiple sex partners, smoking habits, and immune system dysfunctions (3). Cervical cancer is closely linked with human papillomavirus (HPV) infection, and HPVs are detected in 90% of cervical cancer lesions (4-6). While the E6 protein of HPV inactivates p53 and E7 inactivates the retinoblastoma (Rb) tumor suppressor protein, detailed studies on a large number of tumors indicate that viral infection alone is not sufficient for tumor development. Studies have also shown that 20 to 30 million Americans are infected with HPV (7). However, only those in a subset develop cervical cancer. Recently, HPVs have been implicated in the development of head and neck, lung, and breast cancers (8-10).Cystatins are inhibitors of cysteine proteases and are classified into a large superfamily subdivided into three families based on their location, size, and complexity of polypeptide chains (11-13). Cystatin E/M belongs to the type 2 cystatin family (cystatin C, D, E/M, F, S, SA, and SN), whose members are mainly secreted, and most of them are found abundantly in body fluids and tissues. Cystatin E/M is present as an unglycosylated 14-kDa form containing 149 amino acids and a 17-kDa form that is glycosylated. Loss of this protein seems to play a significant role in abnormal skin development (14). A null mutation of the mouse cystatin E/M gene is also correlated with development of the ichq phenotype, characterized by neonatal lethality, abnormal cornification, and desquamation. Cystatin E/M was initially identified as a downregulated transcript in metastatic breast cancers (15,16). A number of studies have implicated cystatin E/M as a human tumor suppressor gene that is inactivated in the cancers of the breast, cervix, prostate, brain, and stomach (17-23). Our studies have also shown that the inactivation of the gene is associated with homozygous deletion, promoter hypermethylation, and somatic mutations in primary tumor samples (19). Cystatin E/M gene is expressed in ductal carcinoma in situ (DCIS) but not in metastatic breast cancer, pointing to inactivation during tumor progression (16)(17)(18)24). Finally, inactivation of cystatin E/M gene is associated with the loss of expression of estrogen and progesterone receptors and HER4, indicating an association with these proteins in the development of invasive breast cancers (25). However, the molecular mechanism of cystatin E/M-mediated tumor cell growth inhibition is not yet understood.Cathepsins include a broad range of proteases, the serine (A

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Soh

Venkatesan

Veena

et al. 2016

Molecular and Cellular Biology

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“…These unique tubes are lined by tumor cells able to transfer red blood to the surrounding tumor tissue, simultaneously providing a path for tumor cell metastasis [9,12]. VM was found in 53 of 89 HCC samples (59.6%).…”

Section: Resultsmentioning

confidence: 99%

“…VM is associated with the host blood circulation to provide a blood supply for tumor tissue, which suggests that VM is functional [6]. Early studies in our laboratory showed that VM was found in HCC and that EMT was involved in the formation of VM [7,8,9]. …”

Section: Introductionmentioning

confidence: 99%

The Expression and Functional Significance of Runx2 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry and Epithelial–Mesenchymal Transition

Cao

Sun

Zhao

et al. 2017

IJMS

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The transcription factor Runx2 has been reported to promote epithelial-mesenchymal transition (EMT) in many tumors. Vasculogenic mimicry (VM) is described as the mimicry of endothelial cells by tumor cells to form microvascular tubes in aggressive tumors. Galectin-3 has been reported to regulate cell invasion, migration, and VM formation; it could be regulated by Runx2. However, the relationship between Runx2, Galectin-3, EMT, and VM has not been studied in hepatocellular carcinoma (HCC). We examined Runx2 expression in 89 human HCC samples and found Runx2 expression was associated with VM. Clinical-pathological data analysis revealed that Runx2 expression was associated with a shorter survival period. Overexpression of Runx2 promoted EMT and enhanced cell migration, invasion, and VM formation in HepG2 cells. Conversely, the downregulation of Runx2 inhibited EMT and reduced cell invasion, migration, and VM formation in SMMC7721. Galectin-3 expression declined following the downregulation of Runx2 in HepG2 cells, and increased in SMMC7721 cells after Runx2 knockdown. We consistently demonstrated that the downregulation of LGALS3 in HepG2-Runx2 cells reduced cell migration; invasion and VM formation; while upregulation of LGALS3 in SMMC7721-shRunx2 cells enhanced cell migration, invasion, and VM formation. The results indicate that Runx2 could promote EMT and VM formation in HCC and Galectin-3 might have some function in this process.

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“…EX-T9592-Lv201) or a negative control (EX-NEG-Lv201) and lentiviral expression plasmids with Nodal shRNA (HSH011861-HIVU6) or a shRNA control (CSHCTR001-HIVU6) were purchased from GeneCopoeia, Inc. The lentivirus-mediated transfection was performed as described previously [56]. MDA-MB-231 cells were transfected with the Nodal shRNA vector (MDA-MB-231-shNodal) or the shRNA control vector (MDA-MB-231-shCon), and MCF-7 cells were transfected with the Nodal cDNA vector (MCF-7-Nodal) or the control (MCF-7-Con).…”

Section: Methodsmentioning

confidence: 99%

Nodal signaling promotes vasculogenic mimicry formation in breast cancer via the Smad2/3 pathway

et al. 2016

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Vasculogenic mimicry (VM) is a nonangiogenesis-dependent pathway that promotes tumor growth and disease progression. Nodal signaling has several vital roles in both embryo development and cancer progression. However, the effects of Nodal signaling on VM formation in breast cancer and its underlying mechanisms are ill-defined. We analyzed the relationship between Nodal signaling and VM formation in one hundred human breast cancer cases and the results showed that the expression of Nodal was significantly correlated with VM formation, tumor metastasis, differentiation grade, TNM stage and poor prognosis. Furthermore, up-regulation of Nodal expression promoted VM formation of breast cancer cells in vitro and in vivo. Knockdown of Nodal expression restrained VM formation. In addition, Nodal induced EMT and up-regulated the expression of Slug, Snail and c-Myc. We found that blocking the Smad2/3 pathway by administering SB431542 inhibited VM formation in breast cancer cell lines and xenografts. Taken together, Nodal signaling through the Smad2/3 pathway up-regulated Slug, Snail and c-Myc to induce EMT, thereby promoting VM formation. Our study suggests that the Nodal signaling pathway may serve as a therapeutic target to inhibit VM formation and improve prognosis in breast cancer patients.

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Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma

Cited by 57 publications

References 41 publications

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

The Expression and Functional Significance of Runx2 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry and Epithelial–Mesenchymal Transition

Nodal signaling promotes vasculogenic mimicry formation in breast cancer via the Smad2/3 pathway

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