BACKGROUND: Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer due to its aggressive characteristics and lack of effective therapeutics. However, the mechanism underlying its aggressiveness remains largely unclear. S-adenosylmethionine decarboxylase proenzyme (AMD1) overexpression occurs specifically in BLBC. Here, we explored the potential molecular mechanisms and functions of AMD1 promoting the aggressiveness of BLBC. METHODS: The potential effects of AMD1 on breast cancer cells were tested by western blotting, colony formation, cell proliferation assay, migration and invasion assay. The spermidine level was determined by high performance liquid chromatography. The methylation status of CpG sites within the AMD1 promoter was evaluated by bisulfite sequencing PCR. We elucidated the relationship between AMD1 and Sox10 by ChIP assays and quantitative real-time PCR. The effect of AMD1 expression on breast cancer cells was evaluated by in vitro and in vivo tumorigenesis model. RESULTS: In this study, we showed that AMD1 expression was remarkably elevated in BLBC. AMD1 copy number amplification, hypomethylation of AMD1 promoter and transcription activity of Sox10 contributed to the overexpression of AMD1 in BLBC. AMD1 overexpression enhanced spermidine production, which enhanced eIF5A hypusination, activating translation of TCF4 with multiple conserved Pro-Pro motifs. Our studies showed that AMD1-mediated metabolic system of polyamine in BLBC cells promoted tumor cell proliferation and tumor growth. Clinically, elevated expression of AMD1 was correlated with high grade, metastasis and poor survival, indicating poor prognosis of breast cancer patients. CONCLUSION: Our work reveals the critical association of AMD1-mediated spermidine-eIF5A hypusination-TCF4 axis with BLBC aggressiveness, indicating potential prognostic indicators and therapeutic targets for BLBC.
Breast Neoplasms , Cell Proliferation , Eukaryotic Translation Initiation Factor 5A , Gene Expression Regulation, Neoplastic , Lysine/analogs & derivatives , Peptide Initiation Factors , RNA-Binding Proteins , Spermidine , Transcription Factor 4 , Humans , Female , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Peptide Initiation Factors/metabolism , Peptide Initiation Factors/genetics , Mice , Animals , Spermidine/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Transcription Factor 4/metabolism , Transcription Factor 4/genetics , Cell Line, Tumor , Promoter Regions, Genetic , Adenosylmethionine Decarboxylase/metabolism , Adenosylmethionine Decarboxylase/genetics , Cell Movement/genetics , DNA Methylation , Prognosis , SOXE Transcription Factors/metabolism , SOXE Transcription Factors/genetics
Basal-like breast cancer (BLBC) is the most aggressive subtype with poor prognosis; however, the mechanisms underlying aggressiveness in BLBC remain poorly understood. In this study, we showed that in contrast to other subtypes, inositol monophosphatase 2 (IMPA2) was dramatically increased in BLBC. Mechanistically, IMPA2 expression was upregulated due to copy number amplification, hypomethylation of IMPA2 promoter and MYC-mediated transcriptional activation. IMPA2 promoted MI-PI cycle and IP3 production, and IP3 then elevated intracellular Ca2+ concentration, leading to efficient activation of NFAT1. In turn, NFAT1 up-regulated MYC expression, thereby fulfilling a positive feedback loop that enhanced aggressiveness of BLBC cells. Knockdown of IMPA2 expression caused the inhibition of tumorigenicity and metastasis of BLBC cells in vitro and in vivo. Clinically, high IMPA2 expression was strongly correlated with large tumor size, high grade, metastasis and poor survival, indicating poor prognosis in breast cancer patients. These findings suggest that IMPA2-mediated MI-PI cycle allows crosstalk between metabolic and oncogenic pathways to promote BLBC progression.
Breast Neoplasms , Humans , Female , Feedback , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Promoter Regions, Genetic
BACKGROUND: Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer because of its aggressive biological characteristics and no effective targeted agents. However, the mechanism underlying its aggressive behavior remain poorly understood. ß1,3-N-acetylglucosaminyltransferase V (B3GNT5) overexpression occurs specifically in BLBC. Here, we studied the possible molecular mechanisms of B3GBT5 promoting the aggressiveness of BLBC. METHODS: The potential effects of B3GNT5 on breast cancer cells were tested by colony formation, mammosphere formation, cell proliferation assay, flow cytometry and Western blotting. The glycosylation patterns of B3GNT5 and associated functions were determined by Western blotting, quantitative real-time PCR and flow cytometry. The effect of B3GNT5 expression on BLBC was assessed by in vitro and in vivo tumorigenesis model. RESULTS: In this study, we showed that B3GNT5 copy number amplification and hypomethylation of B3GNT5 promoter contributed to the overexpression of B3GNT5 in BLBC. Knockout of B3GNT5 strongly reduced surface expression of SSEA-1 and impeded cancer stem cell (CSC)-like properties of BLBC cells. Our results also showed that B3GNT5 protein was heavily N-glycosylated, which is critical for its protein stabilization. Clinically, elevated expression of B3GNT5 was correlated with high grade, large tumor size and poor survival, indicating poor prognosis of breast cancer patients. CONCLUSIONS: Our work uncovers the critical association of B3GNT5 overexpression and glycosylation with enhanced CSCs properties in BLBC. These findings suggest that B3GNT5 has the potential to become a prognostic marker and therapeutic target for BLBC.
Antineoplastic Agents , Breast Neoplasms , Antineoplastic Agents/therapeutic use , Breast Neoplasms/pathology , Female , Glycosylation , Humans , Neoplastic Stem Cells/pathology
Polydatin, an active ingredient from the roots of Polygonum cuspidatum, is considered to have protective effects on the cardiovascular system and liver. In this study, we demonstrated that polydatin has antitumor activity against human cervical cancer. Polydatin efficiently inhibited cervical cancer cell proliferation by regulating cell cycle-related proteins including p21, p27, CDK2, CDK4, Cyclin D1, and Cyclin E1. Furthermore, polydatin suppressed cell invasion and migration by regulating epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, Snail and Slug. The c-Myc, as a proto-oncogene, is considered to be closely associated with the proliferation and metastasis of tumor cells. After polydatin treatment, the protein expression of c-Myc showed a significant decrease. Based on these data, we overexpressed c-Myc in cervical cancer cells and observed that the overexpression of c-Myc rescued the inhibitory effect of polydatin on cell proliferation and metastasis. These results indicated that polydatin can inhibit cell proliferation and metastasis through suppressing the c-Myc expression in human cervical cancer.
BACKGROUND: Nuclear casein kinase and cyclin-dependent kinase substrate (NUCKS), a novel gene first reported in 2001, is a member of the high mobility group (HMG) family. Although very little is known regarding the biological roles of NUCKS, emerging clinical evidence suggests that the NUCKS protein can be used as a biomarker and therapeutic target in various human ailments, including several types of cancer. METHODS: We first assessed the potential correlation between NUCKS expression and gastric cancer prognosis. Then functional experiments were conducted to evaluate the effects of NUCKS in cell proliferation, cell cycle, apoptosis and autophagy. Finally, the roles of NUCKS on gastric cancer were examined in vivo. RESULTS: We found that NUCKS was overexpressed in gastric cancer patients with poor prognosis. Through manipulating NUCKS expression, it was observed to be positively associated with cell proliferation in vitro and in vivo. NUCKS knockdown could induce cell cycle arrest and apoptosis. Then further investigation indicated that NUCKS knockdown could also significantly induce a marked increase in autophagy though the mTOR-Beclin1 pathway, which could be was rescued by NUCKS restoration. Moreover, silencing Beclin1 in NUCKS knockdown cells or adding rapamycin in NUCKS-overexpressed cells also confirmed these results. CONCLUSIONS: Our findings revealed that NUCKS functions as an oncogene and an inhibitor of autophagy in gastric cancer. Thus, the downregulation or inhibition of NUCKS may be a potential therapeutic strategy for gastric cancer.
Beclin-1/genetics , Nuclear Proteins/genetics , Phosphoproteins/genetics , Stomach Neoplasms/genetics , TOR Serine-Threonine Kinases/genetics , Animals , Autophagy/genetics , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Disease-Free Survival , Female , Heterografts , Humans , Kaplan-Meier Estimate , Male , Mice , Signal Transduction/genetics , Stomach Neoplasms/pathology
Infection with human papillomavirus (HPV) is one of the main causes of malignant neoplasms, especially cervical, anogenital, and oropharyngeal cancers. Although we have developed preventive vaccines that can protect from HPV infection, there are still many new cases of HPV-related cancers worldwide. Early diagnosis and therapy are therefore important for the treatment of these diseases. As HPVs are the major contributors to these cancers, it is reasonable to develop reagents, kits, or devices to detect and eliminate HPVs for early diagnosis and therapeutics. Immunological methods are precise strategies that are promising for the accurate detection and blockade of HPVs. During the last decades, the mechanism of how HPVs induce neoplasms has been extensively elucidated, and several oncogenic HPV early proteins, including E5, E6, and E7, have been shown to be positively related to the oncogenesis and malignancy of HPV-induced cancers. These oncoproteins are promising biomarkers for diagnosis and as targets for the therapeutics of HPV-related cancers. Importantly, many specific monoclonal antibodies (mAbs), or newly designed antibody mimics, as well as new immunological kits, devices, and reagents have been developed for both the immunodiagnosis and immunotherapeutics of HPV-induced cancers. In the current review, we summarize the research progress in the immunodiagnosis and immunotherapeutics based on HPV for HPV-induced cancers. In particular, we depict the most promising serological methods for the detection of HPV infection and several therapeutical immunotherapeutics based on HPV, using immunological tools, including native mAbs, radio-labelled mAbs, affitoxins (affibody-linked toxins), intracellular single-chain antibodies (scFvs), nanobodies, therapeutical vaccines, and T-cell-based therapies. Our review aims to provide new clues for researchers to develop novel strategies and methods for the diagnosis and treatment of HPV-induced tumors.
Neoplasms/diagnosis , Neoplasms/therapy , Neoplasms/virology , Papillomavirus Infections/complications , Papillomavirus Infections/diagnosis , Papillomavirus Infections/therapy , Humans , Immunologic Tests/methods , Immunotherapy/methods , Papillomaviridae
Purpose: Alkaloids are naturally occurring chemical compounds that are widely distributed in plants, and have pharmaceutical values and low toxicity. In recent years, some of them have been demonstrated to be promising therapeutic drug candidates for cancer treatment. Herein, we tried to explore the antitumor effect of dehydrocorydaline (DHC), a natural alkaloid isolated from Corydalis, on malignant melanoma. Methods: We treated two malignant metastatic melanoma cell lines, A375 and MV3, and a normal melanocyte cell line, PIG1, with various concentrations of DHC for set amounts of time, and detected cell proliferation, migration, and invasion by using MTT, BrdU, transwell, Western blot and soft agar assay in vitro and tumorigenicity in the xenografts in vivo. Results: Our results showed that DHC dramatically blocked cell proliferation and led to cell cycle arrest at G0/G1 phase and downregulated the expressions of cell cycle regulators CDK6 and Cyclin D1 in melanoma cells. However, DHC had little inhibitory effect on normal melanocyte cell line PIG-1. Meanwhile, DHC suppressed cell invasion and migration through modulating the epithelial-mesenchymal transition (EMT) markers including E-cadherin, vimentin, as well as ß-catenin. In addition, DHC also significantly attenuated tumor growth in vivo. The expressions of cell cycle-related and metastasis-related proteins were further confirmed by immunohistochemical staining in the xenografts. Importantly, MEK1/2-ERK1/2 cascade was inactivated after DHC treatment and ERK activator t-butylhydroquinone (tBHQ) treatment rescued DHC-induced cell proliferation inhibition. Conclusions: Our results indicated that DHC inhibited cell proliferation and migration/invasion via inactivating MAPK signaling, and showed that DHC might be a potential novel drug to treat malignant melanoma.
