Staphylococcal Nuclease Domain-containing 1 Research Articles

Overcoming MTDH and MTDH-SND1 complex: driver and potential therapeutic target of cancer

<p class="MsoNormal" style="margin-top: 12pt; text-align: justify;"><span style="font-family: arial, helvetica, sans-serif;"><span lang="EN-US">Metadherin (MTDH), also known as LYRIC or AEG-1, is an oncogene that enhances tumor progression, metastasis, drug resistance, and immune escape in various cancers by modulating multiple oncogenic pathways, including </span><span lang="EN-US">NF-κB, PI3K/AKT, Wnt/β-catenin, MAPK, and AMPK</span><span lang="EN-US">. Due to the unknown of the complete structure of MTDH, the deep mechanisms of MTDH and selective inhibitors targeting MTDH remain to be explored. The Protein-Protein interaction (PPI) with the Staphylococcal nuclease domain containing 1 (SND1) is a crucial mechanism underlying the function of MTDH. Current studies have demonstrated that inhibitors, including antisense oligonucleotides, peptides, and small molecules targeting MTDH or MTDH-SND1 interactions, provide novel strategies to inhibit the oncogenetic effects of MTDH. This review summarizes and discusses the structure, function, and regulation of MTDH in cancers, providing the potential therapeutic perspectives of MTDH or MTDH-SND1 PPI for drug discovery.</span></span></p>

Cheminformatics and biomolecular dynamics studies towards the discovery of anti-staphylococcal nuclease domain-containing 1 (SND1) inhibitors to treat metastatic breast cancer

Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein–protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score −10.25 kcal/mol, −9.65 kcal/mol and −9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of −19.25 kcal/mol, −27.03 kcal/mol, −34.6 kcal/mol and −29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was −20.45 kcal/mol, −27.89 kcal/mol, −36.41 kcal/mol and –32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity.

Identification of Small Inhibitors for Human Metadherin, an Oncoprotein, through in silico Approach.

Cancer is a disease that takes lives of thousands of people each year. There are more than 100 different types of cancers known to man. This fatal disease is one of the leading causes of death today. Astrocyte elevated gene-1(AEG-1)/Metadherin (MTDH) activates multiple oncogenic signaling pathways and leads to different types of cancers. MTDH interacting with staphylococcal nuclease domain containing 1(SND1) supports the survival and growth of mammary epithelial cells under oncogenic conditions. Silencing MTDH or SND1 individually or disrupting their interaction compromises the tumorigenic potential of tumor-initiating cells. The aim of our present study was to investigate novel interactions of staphylococcal nuclease domain containing 1 (SND1) binding domain of AEG-1/MTDH with different lead compounds through molecular docking approach using MOE software. Molecular docking was done by docking the ChemBridge database against important residues of MTDH involved in interaction with SND1. After docking the whole ChemBridge database, the top 200 interactive compounds were selected based on docking scores. After applying Lipinski's rule, all the remaining chosen compounds were studied on the basis of binding affinity, binding energy, docking score and protein-ligand interactions. Finally, 10 compounds showing multiple interactions with different amino acid residues were selected as the top interacting compounds. Three compounds were selected for simulation studies after testing these compounds using topkat toxicity and ADMET studies. The simulation study indicated that compound 32538601 is a lead compound for inhibiting MTDH-SND1 complex formation. These novels, potent inhibitors of MTDH-SND1 complex can ultimately help us in controlling cancer up to some extent.

Exploring binding modes of the selected inhibitors to SND1 by all-atom molecular dynamics simulations

Breast cancer is the leading cause of cancer-related deaths in women. Previous studies have indicated that disrupting the interaction between Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) can inhibit breast cancer development. Understanding the binding mode of small molecule inhibitors with SND1 is of great significance for designing drugs targeting the MTDH-SND1 complex. In this study, we conducted all-atom molecular dynamics (MD) simulations in solution and performed binding energy calculations to gain insights into the binding mechanism of small molecules to SND1. The binding site of SND1 for small molecules is relatively rigid, and the binding of the small molecule and the mutation of key residues have little effect on the conformation of the binding site. SND1 binds more tightly to C26-A6 than to C26-A2, as C26-A2 undergoes a 180° directional change during the simulation process. The key residue mutations have a direct effect on the position and orientation of small molecule in the binding site. The key residues make primary contributions to the binding energy through van der Waals interaction and nonpolar solvation energy, although the contribution from nonpolar solvation is relatively minor. The key residue mutations also affect the formation of hydrogen bonds and ultimately the stability of the small molecule-SND1 complex. Communicated by Ramaswamy H. Sarma

Unraveling Key Signaling Pathways Altered in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is becoming one of the major health problems, and the leading cause of cancer-related mortality globally. Its multifactorial risk factors remain as paramount challenges to the treatment of this deadly disease. The conventionally known risk factors that trigger HCC include hepatitis C virus (HCV), hepatitis B virus (HBV), excess alcohol consumption, and environmental toxins, such as aflatoxin, aristolochic acid, etc. All these risk factors activate the oncogenic signaling in the liver, and transform the normal liver into an HCC liver. Recently, globalization and the Western sedentary lifestyle have newly emerged as risk factors for HCC, which include obesity, metabolic syndrome, and associated clinical and pathological modalities. In addition, a number of cellular signaling pathways are derailed in HCC, and these pathways, which are altered in HCC, are known to be directly controlled by oncogenes, such as KRAS, BRAF, c-MYC, astrocyte elevated gene-1 (AEG-1), staphylococcal nuclease domain containing 1 (SND1), late SV40 factor (LSF), apoptosis-antagonizing transcription factor (AATF), WNT/β-catenin, TGF-β, etc. All these oncogenes activate the oncogenic signaling in HCC, and suppress the important cellular tumor suppressor protein activity, playing a prominent role in hepatocarcinogenesis, and its development and progression. The present review established a novel interconnected network between all these oncogene-associated proteins, in order to determine its role in deregulating normal cellular signaling pathways, and transforming these into oncogenic signaling. A number of these oncogenes regulate the miRNA-RISC-associated oncogenic signaling, and trigger oncogenic miRNA singling by downregulating various tumor suppressor genes. Therefore, therapeutically targeting these oncogenes and associated proteins would aid in the development of new drugs to treat HCC.

Metadherin (AEG-1/MTDH/LYRIC) expression: Significance in malignancy and crucial role in colorectal cancer.

Metadherin (AEG-1/MTDH/LYRIC) is a 582-amino acid transmembrane protein, encoded by a gene located at chromosome 8q22, and distributed throughout the cytoplasm, peri-nuclear region, nucleus, and nucleolus as well as the endoplasmic reticulum (ER). It contains several structural and interacting domains through which it interacts with transcription factors such as nuclear factor-κB (NF-κB), promyelocytic leukemia zinc finger (PLZF), staphylococcal nuclease domain containing 1 (SND1) and lung homing domain (LHD). It is regulated by miRNAs and mediates its oncogenic function via activation of cell proliferation, survival, migration and metastasis, as well as, angiogenesis and chemoresistance via phosphatidylinositol-3-kinase/AKT (PI3K/AKT), NF-κB, mitogen-activated protein kinase (MAPK) and Wnt signaling pathways. In this chapter, metadherin is reviewed highlighting its role in mediating growth, metastasis and chemoresistance in colorectal cancer (CRC). Metadherin, as well as its variants, and antibodies are associated with CRC progression, poorer prognosis, decreased survival and advanced clinico-pathology. The potential of AEG-1/MTDH/LYRIC as a diagnostic and prognostic marker as well as a therapeutic target in CRC is explored.

Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.

Metastatic breast cancer is leading health burden worldwide. Previous studies have shown that Metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with Staphylococcal nuclease domain-containing 1 (SND1) which is required to sustain breast cancer progression in established tumors. We performed a small molecule compound screening to identify a class of specific inhibitors that disrupt the protein-protein interaction between MTDH-SND1, and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis, and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer. Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.

Despite the increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that Metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with Staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing anti-tumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 mRNAs, which encode key components of the antigen presentation machinery. Following small molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-PD-1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune checkpoint blockade therapy responses in metastatic breast cancer.

PAX5 activates telomerase activity and proliferation in keloid fibroblasts by transcriptional regulation of SND1, thus promoting keloid growth in burn-injured skin.

Staphylococcal nuclease domain-containing 1 (SND1) that functioned as an oncogene in a variety of tumors was upregulated in burn-injured skin tissues, and this study aims to investigate the effect of SND1 on keloid and elucidate the underlying mechanism. Keloid fibroblasts (KFs) and normal skin fibroblasts (NFs) were isolated from the keloid tissues and adjacent normal skin tissues of keloid patients. The SND1 expression was assessed in keloid tissues and KFs with Western blot assay. Gain- and loss-of-function experiments were performed to investigate the role of SND1 in proliferation, colony formation, telomerase activity, expression of fibrogenic genes and production of pro-inflammatory factors in KFs. Chromatin immunoprecipitation (CHIP) and Dual-luciferase reporter gene assays were used to verify the interaction of Paired-box gene 5 (PAX5) on SND1 promoter. Then, a series of rescue experiments were performed to verify the effects of SND1 overexpression on PAX5 knockdown-mediated KF functions. Finally, the role of SND1 in keloid formation in vivo was validated in mice with keloid implantation. SND1 was upregulated in keloid tissues and KFs. SND1 positively regulated proliferation, colony formation, telomerase activity, production of pro-inflammatory factors and expression of fibrogenic genes. PAX5 directly bound to the SND1 promoter to transcriptionally regulate SND1 expression and positively regulated SND1-mediated KF functions via the ERK/JNK pathway. In vivo assay further demonstrated that SND1 displayed a positive effect on keloid formation. SND1 transcriptionally regulated by PAX5 promotes keloid formation through activating telomerase activity via the ERK/JNK signaling pathways, which provides a promising therapeutic target for clinical treatment of burned skin keloid.

Circ SMARCA5 Inhibited Tumor Metastasis by Interacting with SND1 and Downregulating the YWHAB Gene in Cervical Cancer

Cervical cancer is one of the diseases that seriously endanger women’s health. Circular RNA plays an important role in regulating the occurrence and development of cervical cancer. Here, we investigated the mechanisms of circ SMARCA5 in the development of cervical cancer. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) results showed that the expression of SMARCA5 was downregulated in cervical cancer tissues and cell lines. Then we found that overexpression of SMARCA5 inhibited proliferation and invasion, but promoted apoptosis in cervical cancer cells. These were detected by Cell Counting Kit-8, Transwell, and Annexin V-fluorescein isothiocyanate/propidium iodide detection kit, respectively, and the expression of the apoptosis-related proteins was determined by western blotting. Then we predicted that SMARCA5 combined with Staphylococcal nuclease domain-containing 1 (SND1) by starBase, and verified by RNA pull-down assay. To further reveal the molecular mechanisms of SMARCA5 in the progression of cervical cancer, the interaction protein of SND1 was predicted by STRING, and the interaction was verified by co-immunoprecipitation assay. Then, the effects of SND1 or YWHAB on the development of cervical cancer were detected by the gain and loss function test, and we found that knockdown of SND1 or YWHAB reversed the effects of SMARCA5 short interfering RNA on proliferation, invasion, and apoptosis of cervical cancer cells. Overexpression of SMARCA5 inhibited cervical cancer metastasis in vivo. Our results showed that overexpression of circ SMARCA5 inhibits the binding of SND1 to YWHAB, and inhibits the proliferation and invasion, but promotes apoptosis in cervical cancer cells, thus inhibiting the metastasis of cervical cancer.

Linc00668 Promotes Invasion and Stem Cell-Like Properties of Breast Cancer Cells by Interaction With SND1.

Long non-coding RNAs (lncRNAs) are reported to be involved in breast cancer progression. Herein, we observed that the expression of Linc00668 was increased in breast cancer compared to normal tissue. The patients with high Linc00668 expression exhibited an association with a higher metastatic risk. We demonstrated that forced expression of Linc00668 enhanced, whereas depletion of Linc00668 diminished invasion and self-renewal of breast cancer cells as well as resistance to doxorubicin (Dox). Further mechanistic studies revealed that Linc00668 associated with staphylococcal nuclease domain-containing 1 (SND1) and regulated the expression of downstream genes. Linc00668 depletion led to reduced expression of the downstream target of SND1 and further attenuated the self-renewal capacity of breast cancer cells. Our observations suggest that Linc00668 promotes metastasis, and chemotherapeutic resistance in breast cancer by interacting with SND1. Therefore, Linc00668 may serve as a potential therapeutic modulator in breast cancer treatment.

PTB-AS, a Novel Natural Antisense Transcript, Promotes Glioma Progression by Improving PTBP1 mRNA Stability with SND1.

Glioma, the most common primary malignancy in the brain, has high recurrence and lethality rates, and thus, elucidation of the molecular mechanisms of this incurable disease is urgently needed. Poly-pyrimidine tract binding protein (PTBP1, also known as hnRNP I), an RNA-binding protein, has various mechanisms to promote gliomagenesis. However, the mechanisms regulating PTBP1 expression are unclear. Herein, we report a novel natural antisense noncoding RNA, PTB-AS, whose expression correlated positively with PTBP1 mRNA. We found that PTB-AS significantly promoted the proliferation and migration invivo and invitro of glioma cells. PTB-AS substantially increased the PTBP1 level by directly binding to its 3' UTR and stabilizing the mRNA. Furthermore, staphylococcal nuclease domain-containing 1 (SND1) dramatically increased the binding capacity between PTB-AS and PTBP1 mRNA. Mechanistically, PTB-AS could mask the binding site of miR-9 in the PTBP1-3' UTR; miR-9 negatively regulates PTBP1. To summarize, we revealed that PTB-AS, which maintains the PTBP1 level through extended base pairing to the PTBP1 3' UTR with the assistance of SND1, could significantly promote gliomagenesis.

SND1 promotes the proliferation of osteosarcoma cells by upregulating COX‑2/PGE2 expression via activation of NF‑κB

Osteosarcoma is the most frequent primary bone tumor. Staphylococcal nuclease domain‑containing1 (SND1) is a multifunctional protein that plays important roles in tumor development and progression. Overexpression of SND1 has been found in several malignancies, however, its expression and function in osteosarcoma is largely unknown. In the present study, we firstly examined the expression of SND1 in 12pairs of osteosarcoma and healthy bones by immunoblotting and real time‑PCR. The results revealed that osteosarcoma tissues expressed significantly high SND1 mRNA and protein expression compared to normal bone tissues. Next, we stably overexpressed SND1 ORF in MG‑63 cells and further defined the biological function of SND1 in osteosarcoma by flow cytometry, cell proliferation and invivo assays. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth invitro and invivo. Furthermore, the non‑targeted metabolic profiling, ELISA and luciferase reporter assays were performed on stable overexpressing cells and blood samples to elucidate the underlying mechanisms of SND1‑mediated oncogenic features. The results revealed that SND1 increased the production of arachidonic acid PGE2. The serum PGE2 expression level had a significant positive association with the SND1 mRNA expression level in osteosarcoma tissues. The SND1 overexpression‑stimulated cell proliferation was enhanced by exogenous addition of PGE2. Additionally, we found that SND1 upregulated PGE2 expression through the NF‑κB/cyclooxygenase‑2 (COX‑2) pathway. In summary, our findings revealed the mechanisms of SND1 involvement in osteosarcoma tumor development, and support the targeting of SND1 as a new anti‑tumor strategy for patients with osteosarcoma. In addition, SND1 may act as a potential biomarker of the therapeutic strategies utilizing COX‑2 inhibitors.

SND1 expression in breast cancer tumors is associated with poor prognosis.

Staphylococcal nuclease domain-containing 1 (SND1) expression is crucial for breast cancer metastasis; however, the clinical implications of SND1 expression in breast cancer remain unclear. This study investigated the relationship of SND1 protein expression both with metastasis and the prognoses of 144 breast cancer patients over a 10-year follow-up. Chi-square tests revealed that the percentages of positive SND1 expression in breast cancer tumors were significantly associated with larger tumor size (>2cm, P = 0.043), higher clinical TNM stage (P = 0.003), and positive lymph node metastasis (P = 0.001). Breast cancer patients with positive SND1 expression had a significantly shorter overall survival and disease-free survival than those with negative SND1 expression (P <0.01). Multiple Cox regression analysis indicated that SND1 expression is an independent risk factor for shorter disease-free survival (hazard ratio = 1.97, P = 0.014). The percentages of SND1 expression in metastatic breast cancers were significantly higher than that in primary tumors in 30 patients with advanced breast cancer (P = 0.016). Therefore, SND1 protein expression is significantly associated with breast cancer metastasis and may serve as a biomarker for prognosis of breast cancer patients.

SND1 acts as a novel gene transcription activator recognizing the conserved Motif domains of Smad promoters, inducing TGFβ1 response and breast cancer metastasis.

As an AEG-1/MTDH/LYRIC-binding protein, Staphylococcal nuclease domain-containing 1 (SND1) is upregulated in numerous human cancers where it has been assigned multiple functional roles. In this study, we discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1 (TGFβ1) signaling pathway, which promotes metastasis in breast cancer. We illustrated that SND1 physically associated with and recruited the histone acetylase GCN5 to the promoter regions of Smad2/3/4, and consequently enhanced the gene transcriptional activation of Smad2/3/4, which are essential downstream regulators in the TGFβ1 pathway. An electrophoretic mobility shift assay experiment further verified that SND1 could recognize the conserved domains (motifs 1 and 2) in the promoter regions of the Smad genes. Glutathione S-transferase (GST) pulldown assays indicated that the tudor domain of SND1 was responsible for the recruitment of GCN5, which increased histone H3K9 acetylation. Consistent with these results, a loss-of-function of SND1 reduced the protein level of Smads and the phosphorylation of R-Smads, thereby attenuating the R-Smad/Co-Smad depended transcription and, as a result, inhibited TGFβ signaling activation.

Correlated overexpression of metadherin and SND1 in glioma cells.

Glioma is the most common primary brain tumor with poor prognosis. Effective treatment of glioma remains a big challenge due to complex pathogenic mechanisms. Previous studies have shown that metadherin (MTDH) and its interacting protein staphylococcal nuclease domain containing 1 (SND1) are overexpressed in many solid tumors. To elucidate the role of MDTH and SND1 in the pathogenesis of glioma, we examined the expression of MTDH and SND1 in primary glioma tissues and found that both MTDH and SND1 were highly expressed, with similar expression patterns. Co-expression of MTDH and SND1 was associated with advanced glioma grades. In addition, we detected the interaction between MTDH and SND1 in cultured glioma cell lines. MTDH could promote the expression of p65 and SND1 in glioma cells. However, enhanced SND1 expression by MTDH was abolished by the inhibition of p65. In conclusion, we demonstrated high expression levels MTDH and SND1 in primary glioma tissues. MTDH might promote glioma by inducing SND1 expression through the activation of NF-κB pathway. MTDH and SND1 may serve as the indicator of malignancy and prognosis as well as therapeutic targets for patients with glioma.

MiR-361-5p inhibits colorectal and gastric cancer growth and metastasis by targeting staphylococcal nuclease domain containing-1.

MicroRNAs (miRs) function as key regulators of gene expression and their deregulation is associated with the carcinogenesis of various cancers. In the present study, we investigated the biological role and mechanism of miR-361-5p in colorectal carcinoma (CRC) and gastric cancer (GC). We showed that microRNA-361-5p (miR-361-5p) was down-regulated in CRC and GC in comparison to the controls. Meanwhile, the expression levels of miR-361-5p negatively correlated with lung metastasis and prognosis in clinical CRC patients. Overexpression of miR-361-5p markedly suppressed proliferation, migration and invasion of cancer cells. Additionally, this phenotype could be partially rescued by the ectopic expression of staphylococcal nuclease domain containing-1 (SND1). SND1 was identified as a target of miR-361-5p using bioinformatics analysis and in vitro luciferase reporter assays. In turn, SND1 bound to pre-miR-361-5p and suppressed the expression of miR-361-5p, thus exerting a feedback loop. Most interestingly, in vivo studies showed that restoration of miR-361-5p significantly inhibited tumor growth and especially the lung metastasis in nude mice. Therefore, it could be concluded that miR-361-5p functions as a tumor-suppressive miRNA through directly binding to SND1, highlighting its potential as a novel agent for the treatment of patients with CRC and GC.

Structural Insights into the Tumor-Promoting Function of the MTDH-SND1 Complex

Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.

Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGFβ signaling

Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in human hepatocellular carcinoma (HCC) patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R) levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGFβ signaling pathway, promoting epithelial–mesenchymal transition (EMT) and migration and invasion by human HCC cells. A positive correlation was observed between SND1 and AT1R expression levels in human HCC patients. Small molecule inhibitors of SND1, alone or in combination with AT1R blockers, might be an effective therapeutic strategy for late-stage aggressive HCC.

SND1 Affects Proliferation of Hepatocellular Carcinoma Cell Line SMMC‐7721 by Regulating IGFBP3 Expression

Staphylococcal nuclease domain containing 1 (SND1) is a ubiquitously expressed multifunctional protein involved in transcriptional regulation, RNA splicing and RNA metabolism. Ectopic expression of SND1 has been observed in various tumors including colon cancer, breast cancer, prostate cancer and hepatocellular carcinoma (HCC), indicating a positive role of SND1 in tumor initiation and progression. However, the exact role of SND1 in cancers has not been thoroughly investigated. In the present study, we investigated the role of SND1 in HCC. Immunohistochemistry analysis revealed that the expression level of SND1 was higher in HCC tissues than in adjacent nontumor tissues. Stable knock-down of SND1, performed on the HCC cell line SMMC-7721 using shRNA lentiviral expression system, led to reduced cell proliferation, clone formation and tumor formation in nude mice. The insulin-like growth factor (IGF) signaling pathway was frequently dysregulated in HCC, which could facilitate tumor progression. Screening of gene expression levels of the IGF pathway, using real-time PCR, revealed that a decrease in SND1 expression could increase the expression of IGF-binding protein 3 (IGFBP3), which can negatively regulate activation of the IGF pathway by restricting interactions between IGF and IGF receptors. Results from previous studies showed that the downregulation of IGFBP3 expression is a common feature in HCC, and the upregulation of IGFBP3 expression could suppress HCC cells proliferation. We further confirmed that stable knock-down of IGFBP3 could promote SMMC-7721 cells proliferation. Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway.