LncRNA MAGI2-AS3 inhibits hepatocellular carcinoma cell proliferation and migration by targeting the miR-374b-5p/SMG1 signaling pathway

Long noncoding RNAs (lncRNAs) have been proven to play critical roles in cancer progression. Recently, lncRNA MAGI2-AS3 has been revealed to be a tumor suppressor and inhibit cell growth by targeting the Fas/FasL signalling pathway in breast cancer. However, the role and underlying mechanism of MAGI2-AS3 in hepatocellular carcinoma (HCC) remain largely unknown. In the current study, we found that MAGI2-AS3 expression is downregulated in HCC tissues and closely associated with some clinical characteristics (tumor size, lymph node metastasis, and TNM stage) and poor overall survival. Overexpression of MAGI2-AS3 inhibits HCC cell proliferation and migration in vitro, while impedes tumor growth in vivo accordantly. In addition, our data suggest that MAGI2-AS3 could function as an endogenous sponge of miR-374b-5p by directly binding to it and suppressing its expression. Furthermore, miR-374b-5p upregulation could restore the inhibitory effect of MAGI2-AS3 on HCC cells processes. Moreover, suppressor with morphogenetic effect on genitalia family member 1 (SMG1) is positively regulated by MAGI2-AS3 via absorbing miR-374b-5p in HCC cells. More important, SMG1 knockdown reverses the suppressive function of MAGI2-AS3 in HCC cell processes. Taken together, we reveal a functional MAGI2-AS3/miR-374b-5p/SMG1 axis that suppresses HCC progression, potently suggesting a new road for HCC treatment.     

Involvement of SEPT4_i1 in hepatocellular carcinoma: SEPT4_i1 regulates susceptibility to apoptosis in hepatocellular carcinoma cells

SEPT4 belongs to the Septin family with multiple functions in cell division, cytoskeletal organization and other processes. This study aims to investigate the relationship between SEPT4_i1 isoform and human hepatocellular carcinoma (HCC). We showed that over-expression of SEPT4_i1 in HCC cells was able to sensitize cells to serum starvation-induced apoptosis. By contrast, knockdown of SEPT4_i1 expression in HCC cells was able to rescue cells from apoptosis induced by serum deprivation and to promote cell growth. Expressional analysis of SEPT4_i1 in tumor tissues further revealed that SEPT4_i1 was significantly down-regulated in human HCC tissues. Taken together, these data suggests a tumor suppressor role of SEPT4_i1 in HCC through regulating HCC cell apoptosis.     

肿瘤转移抑制基因BRMS1的表达分析及机制研究进展

乳腺癌转移抑制基因1(BRMS1)是一个有活性的肿瘤转移抑制基因,参与抑制乳腺癌、黑素瘤、鼻咽癌、非小细胞肺癌、卵巢癌等恶性肿瘤的转移。BRMS1编码蛋白主要通过转录调控转移相关靶基因,参与调节细胞凋亡、细胞通讯、肿瘤血管新生等多种细胞事件。从BRMS1基因的分子结构、表达调控、生物学功能以及转移抑制机理等方面对BRMS1的研究进展做简要回顾。     

Effect of BRMS1 on Tumorigenicity and Metastasis of Human Rectal Cancer

Breast cancer metastasis suppressor gene-1 (BRMS1) is newly discovered tumor metastasis gene, which has been reported to play an important role in the progression of human tumor. However, its role in rectal cancer has never been investigated. In this present study, we evaluated the associated of BRMS1 with colorectal cancer, its value in prognosis, and its role in metastasis of rectal cancer. BRMS1 expression examined in 80 patients and the role of BRMS1 in metastasis was studied using mice model. Our results showed that BRMS1 expression was significantly associated with clinicopathological parameters in rectal cancer patients and overexpression of BRMS1 in rectal cancer xenograft led to decreased growth, invasiveness and metastasis. Our findings indicate that high expression of BRSM1 in rectal cancer plays an essential role in tumor progression.     

Purification and characterisation of the breast cancer metastasis suppressor, BRMS1

The breast cancer metastasis suppressor 1 (BRMS1) is a member of a family of proteins that actively suppress tumour metastasis. Understanding BRMS1 mediated metastasis suppression is critical to the development of new therapies designed to prevent and treat patients with late stage breast cancer. To aid research into the functional aspects that underpin BRMS1 mediated metastasis suppression we have expressed and purified recombinant BRMS1 and produced BRMS1 polyclonal antibodies. Using these antibodies to immunoprecipitate endogenous BRMS1 containing complexes from MCF7 breast cancer cell lines we have identified, by mass spectrometry, the small heat shock protein Hsp27 in complex with BRMS1. We also show that the expression of both BRMS1 and Hsp27 are inversely correlated with metastatic potential.     

Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1

We recently identified a novel metastasis suppressor gene, BRMS1, in breast cancer. Since the BRMS1 gene maps to chromosome 11q13.1-q13.2 and since chromosome 11q defects have been described in various stages of human melanoma progression, we hypothesized that BRMS1 may function as a tumor or metastasis suppressor in melanomas as well. Quantitative real-time RT-PCR revealed that BRMS1 mRNA expression was high in melanocytes, considerably reduced in early melanoma-derived cell lines, and barely detectable in advanced/metastatic cell lines. Stable transfectants of BRMS1 in the human melanoma cell lines MelJuSo and C8161.9 did not alter the tumorigenicity of either cell line, but significantly suppressed metastasis compared to vector-only transfectants. Orthotopic tumors continued to express BRMS1, but expression was lost in lung metastases. In vitro morphology, growth rate, and histology of BRMS1 transfectants were similar to controls. BRMS1 transfectants were less invasive in a collagen sandwich assay and had restored homotypic gap junctional intercellular communication (GJIC). Thus, BRMS1 functions as a metastasis suppressor in more than one tumor type (i.e., breast carcinoma and cutaneous melanoma) by modifying several metastasis-associated phenotypes.     

FT Raman spectroscopy in the evaluation of biomarkers of normal and pathological placenta tissue

Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors with high recurrence and metastasis rates. Radiotherapy represents a major therapeutic option for HCC patients. However, the efficacy of radiotherapy has been limited due to the development of intrinsic radioresistance of the tumor cells. Small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3), one member of SUMO pseudogene family, is a novel identified lncRNA that was originally identified to be upregulated in gastric cancer. However, the detailed roles of SUMO1P3 in HCC development remain to be elucidated. Here, the expression of SUMO1P3 in HCC tissues and cells was examined by qRT-PCR. Cell proliferation, colony formation ability, invasion ability, apoptosis, and radiosensitivity were detected by MTT assay, colony formation assay, cell invasion assay, flow cytometry analysis, and survival fraction assay, respectively. We found that SUMO1P3 was significantly upregulated in HCC tissues and cells. Besides, SUMO1P3 was highly expressed in HCC patients with higher TNM stage. Furthermore, SUMO1P3 knockdown markedly suppressed cell proliferation, colony formation ability, and cell invasiveness, promoted apoptosis, and enhanced radiosensitivity of HCC cells. We concluded that the knockdown of SUMO1P3 repressed tumor growth, invasion, promoted apoptosis, and enhanced radiosensitivity in HCC, providing evidence that SUMO1P3 might be a potential novel biomarker and a therapeutic target for HCC.

     

Recent advances in breast cancer metastasis suppressor 1

Metastasis is a complex process divided into a number of steps including detachment of tumor cells from the primary tumor, invasion, migration, intravasation, survival in the vasculature, extravasation, and colonization of the secondary site. Proteins that block metastasis without inhibiting primary tumor formation are known as metastasis suppressors; examples are NM23, Maspin, KAI1, KISS1, and MKK4. Breast cancer metastasis suppressor 1 (BRMS1) was identified as a suppressor of breast cancer metastasis in the late 1990s. In vitro and in vivo studies have confirmed that BRMS1 is a potent metastasis suppressor not limited to breast cancer. However, conflicting clinical observations regarding its role as a metastasis suppressor and its validity as a diagnostic biomarker warrant more in-depth clinical study. In this review, the authors provide an overview of its biology, function, action mechanism and pathological significance.     

Angiopoietin-2, an angiogenic regulator, promotes initial growth and survival of breast cancer metastases to the lung through the integrin-linked kinase (ILK)-AKT-B cell lymphoma 2 (Bcl-2) pathway

The early onsets of breast cancer metastasis involve cell retention, survival, and resistant to apoptosis and subsequent growth at target vascular beds and tissues in distant organs. We previously reported that angiopoietin-2 (Ang2), an angiogenic regulator stimulates MCF-7 breast tumor metastasis from their orthotopic sites to distant organs through the α(5)β(1) integrin/integrin-linked kinase (ILK)/Akt pathway. Here, by using an experimental tumor metastasis model and in vitro studies, we further dissect the underlying mechanism by which Ang2 promotes the initial growth and survival of MCF-7 breast cancer metastasis in the lung of animals. We show that Ang2 increases cell survival and suppresses cell apoptosis through ILK-induced phosphorylation of Akt1, Akt2, and up-regulation of Bcl-2 in breast cancer cells. Inhibition of ILK, Akt1, and Akt2, and their effector Bcl-2 diminishes Ang2-stimulated breast cancer cell survival and Ang2-attenuated apoptosis in vitro, and initial survival and growth of breast cancer metastasis in the lung of animals. Additionally, siRNA knockdown of endogenous Ang2 in three human metastatic breast cancer cell lines also inhibits phosphorylation of Akt, expression of Bcl-2, and tumor cell survival, migration, and increases cell apoptosis. Since increased expression of Ang2 correlates with elevated potential of human breast cancer metastasis in clinic, our data underscore the importance that up-regulated Ang2 not only stimulates breast cancer growth and metastasis at late stages of the process, but is also critical at the initiating stages of metastases onset, thereby suggesting Ang2 as a promising therapeutic target for treating patients with metastatic breast cancer.     

Overexpression of osteopontin in hepatocellular carcinoma and its relationships with metastasis,invasion of tumor cells

Osteopontin (OPN) plays an important role in metastasis and relapse of human cancer. However, the whole story of OPN relating to cancer has been far from clear untill now. To investigate the expression of OPN in hepatocellular carcinoma (HCC) and its relationships with recurrence and metastasis of HCC, normal and malignant liver tissues from patients with HCC were analyzed using immunohistochemical staining. OPN expression was inhibited by small interfering RNA (siRNA) in HCC cells lines, and then colony formation and matrigel invasion were examined. The results showed that expression of OPN was associated with metastasis of HCC with a positive rate of OPN in the tissue of HCC (70.00%), which was highly more obvious than those in paracarcinoma tissue and normal liver tissue (P < 0.01). In HCC cell lines, OPN depletion could reduce formed colony and metastasizing numbers in vitro. In conclusion, Expression of OPN in the tissue of HCC is related to metastasis or metastases. Specific siRNA could decrease expressions of OPN at both mRNA and protein levels, and abates the invasiveness of hepatocellular carcinoma cells, suggesting that OPN might be a promising agent for treatment of metastasis and recurrence of HCC.     

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.     

Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression

Precise cell cycle regulation is critical to prevent aberrant cell proliferation and cancer progression. Cks1 was reported to be an essential accessory factor for SCF^Skp2, the ubiquitin ligase that targets p27^Kip1 for proteasomal degradation; these actions drive mammalian cell transition from G1 to S phase. In this study, we investigated the role played by Cks1 in the growth and progression of human hepatocellular carcinoma (HCC) cells. Silencing Cks1 expression abrogated osteopontin (OPN) expression in a p27^Kip1-dependent manner in Huh7 HCC cells. OPN increased the proliferation, migration and invasion of Huh7 cells. Pharmacological inhibitor studies demonstrated that ERK1/2 signaling is responsible mainly for Cks1-mediated OPN expression. Cks1 appears to regulate ERK1/2 signaling through the expression of dual-specificity phosphatase 16 (DUSP16) because both Cks1 knockdown, which leads to DUSP16 upregulation, and DUSP16 overexpression decreased ERK1/2 phosphorylation and the resulting OPN expression. The same is true for the Cks1-mediated increases in p27^Kip1, suggesting that Cks1 regulates OPN expression through activating ERK1/2 signaling either by suppressing DUSP16 expression or by a p27^Kip1-dependent mechanism. Cks1 and OPN expression levels were significantly higher, but DUSP16 expression levels were significantly lower in HCC tissues than in normal liver tissues. Both Cks1 and OPN expression were negatively correlated with DUSP16 expression, whereas Cks1 expression was positively correlated with OPN expression. Moreover, combined panels for the expression levels of Cks1, DUSP16 and OPN showed significant prognostic power for the risk assessment of HCC patient overall survival. In conclusion, our data propose a novel function for Cks1 as a tumor promoter through the expression of the strongly oncogenic protein OPN in HCC.     

MicroRNA‐301b‐3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4

MicroRNAs (miRNAs) are key regulators in the tumour growth and metastasis of human hepatocellular carcinoma (HCC). Increasing evidence suggests that miR‐301b‐3p functions as a driver in various types of human cancer. However, the expression pattern of miR‐301b‐3p and its functional role as well as underlying molecular mechanism in HCC remain poorly known. Our study found that miR‐301b‐3p expression was significantly up‐regulated in HCC tissues compared to adjacent non‐tumour tissues. Clinical association analysis revealed that the high level of miR‐301b‐3p closely correlated with large tumour size and advanced tumour‐node‐metastasis stages. Importantly, the high miR‐301b‐3p level predicted a prominent poorer overall survival of HCC patients. Knockdown of miR‐301b‐3p suppressed cell proliferation, led to cell cycle arrest at G2/M phase and induced apoptosis of Huh7 and Hep3B cells. Furthermore, miR‐301b‐3p knockdown suppressed tumour growth of HCC in mice. Mechanistically, miR‐301b‐3p directly bond to 3′UTR of vestigial like family member 4 (VGLL4) and negatively regulated its expression. The expression of VGLL4 mRNA was down‐regulated and inversely correlated with miR‐301b‐3p level in HCC tissues. Notably, VGLL4 knockdown markedly repressed cell proliferation, resulted in G2/M phase arrest and promoted apoptosis of HCC cells. Accordingly, VGLL4 silencing rescued miR‐301b‐3p knockdown attenuated HCC cell proliferation, cell cycle progression and apoptosis resistance. Collectively, our results suggest that miR‐301b‐3p is highly expressed in HCC. miR‐301b‐3p facilitates cell proliferation, promotes cell cycle progression and inhibits apoptosis of HCC cells by repressing VGLL4.     

BRMS1 Suppresses Glioma Progression by Regulating Invasion,Migration and Adhesion of Glioma Cells

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in glioma have not been reported. In this study, we investigated whether BRMS1 play a role in glioma pathogenesis. Using the tissue microarray technology, we found that BRMS1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P<0.01, χ² test) and reduced BRMS1 staining is associated with WHO stages (P<0.05, χ² test). We also found that BRMS1 was significantly downregulated in glioma cell lines compared to normal human astrocytes (P<0.01, χ² test). Furthermore, we demonstrated that BRMS1 overexpression inhibited glioma cell invasion by suppressing uPA, NF-κB, MMP-2 expression and MMP-2 enzyme activity. Moreover, our data showed that overexpression of BRMS1 inhibited glioma cell migration and adhesion capacity compared with the control group through the Src-FAK pathway. Taken together, this study suggested that BRMS1 has a role in glioma development and progression by regulating invasion, migration and adhesion activities of cancer cells.     

乳腺癌转移抑制因子BRMS1研究进展

癌转移是导致癌症患者死亡的主要原因, 因此, 研究癌转移的分子机制能为癌症的预后和治疗提供新的方法。癌转移抑制基因是一类只抑制癌细胞的转移而不影响肿瘤的发生与生长的基因。BRMS1是2000年在乳腺癌细胞中发现的癌转移抑制基因。它所编码的蛋白还可以抑制黑素瘤细胞和小鼠乳腺癌细胞的转移。BRMS1定位于核内, 与mSin3-HDAC复合体相互作用, 并且可以改变乳腺癌细胞的connexin表达特征, 从而恢复间隙连接介导的细胞间连接通讯。文章就BRMS1的研究进展做一综述, 对其相关的基因也给予简单的介绍, 并对它可能的作用机制进行了预测。     

Livin promotes progression of breast cancer through induction of epithelial–mesenchymal transition and activation of AKT signaling

The inhibitor of apoptosis proteins (IAP) are closely correlated with proliferation, apoptosis, motility, and metastasis. Livin is the most recently identified IAP, and its role in breast progression remains unknown. In our study, analyses of 50 patients with breast cancer revealed that the positive expression rate of Livin was higher in breast cancer tissues (62%) relative to that in adjacent (35%) and normal tissues (25%). Livin expression in breast cancer correlated with the clinical stage and axillary lymph node metastasis and could be used as a prognostic marker. Our in vitro experiment revealed that Livin was highly expressed in high-invasive MDA-MB-231 cells as compared to low-invasive cells (MCF-7). Suppression of Livin by short-hairpin RNA reduced the Livin expression of MDA-MB-231 cells and subsequently inhibited tumor cell growth, proliferation, and colony formation and induced tumor cell apoptosis, motility, migration, and invasion. Overexpression of Livin in MCF7 cells resulted in increased migration and invasion capabilities of the cells without affecting proliferation and apoptosis. In addition, epithelial–mesenchymal transition (EMT) was induced by Livin expression in breast cancer cell lines. The high level of phosphorylated AKT in MDA-MB-231 cells was suppressed by Livin knockdown. Further, Livin-induced migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or knockdown of AKT expression using small-interfering RNA. In conclusion, Livin serves as an independent prognostic indicator for breast cancer. Livin expression promotes breast cancer metastasis through the activation of AKT signaling and induction of EMT in breast cancer cells both in vitro and in vivo.     

miR‐346 promotes migration and invasion of nasopharyngeal carcinoma cells via targeting BRMS1

The aim of this study is to determine the expression and roles of miR‐346 in nasopharyngeal carcinoma (NPC). We showed that miR‐346 was upregulated in NPC tissues compared with adjacent non‐tumorous nasopharyngeal tissues. Inhibition of miR‐346 significantly attenuated the migration and invasion of NPC cells. Luciferase reporter assay showed that miR‐346 targeted the 3′‐untranslated region (3′‐UTR) of breast cancer metastasis suppressor 1 (BRMS1). Overexpression of miR‐346 suppressed the endogenous expression of BRMS1 in NPC cells. There was a significant negative correlation between miR‐346 and BRMS1 protein expression in NPC tissues (r = ?0.372, P = 0.008). Rescue experiments demonstrated that overexpression of BRMS1 lacking the 3′‐UTR impaired the invasiveness of NPC cells transfected with miR‐346 mimic. Taken together, miR‐346 shows the ability to promote the migration and invasion of nasopharyngeal cancer cells via targeting BRMS1 and represents a potential therapeutic target for NPC.