HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8.

Targeted inhibition of histone deacetylase (HDAC) is one of the potent anticancer therapy approaches. Our data showed that mRNA and protein levels of HDAC1 in breast cancer cells were greater than that in normal fibroblast 3T3 cells and normal epithelial breast MCF10A cells. The mRNA levels of HDAC1 in 75% of breast cancer tissues (18/24) were greater than that in their corresponding adjacent normal tissues. Knockdown of HDAC1 by specific siRNAs can suppress the proliferation and migration of breast cancer cells and inhibit the expression of interleukin-8 (IL-8), while not IL-6. While recombinant IL-8 (rIL-8) can attenuate the suppression effects of si-HDAC1 on the proliferation and migration of breast cancer cells. HDAC1 can positively regulate the transcription and promoter activities of IL-8. While NF-κB and MAPK, two important signals responsible for the transcription of IL-8, did not mediate HDAC1 regulated IL-8 expression. The expression and nuclear translocation of Snail were increased in HDAC1 over expressed breast cancer cells. Targeted inhibition of Snail can attenuate HDAC1 over expression induced cell proliferation and migration. Collectively, our data showed that HDAC1 can trigger the proliferation and migration of breast cancer cells via activation of Snail/IL-8 signals.

IL-8 Is Involved in Estrogen-Related Receptor α-Regulated Proliferation and Migration of Colorectal Cancer Cells.

BACKGROUND AND AIMS: Studies revealed that estrogenic signals were involved in the development of colorectal cancer (CRC), while the roles of estrogen related receptor (ERR) on the progression of CRC have not been well illustrated. Its roles on the development of CRC were investigated. METHODS: The expression of ERRα/ß/γ in CRC cells were measured. The effects of ERRα on cell proliferation, migration and expression of cytokines were investigated accordingly. RESULTS: Our data revealed that the expression of ERRα, while not ERRß or ERRγ, was significantly increased in CRC cells and clinical CRC tissues. Both the inverse agonist of ERRα (XCT-790) and si-ERRα can inhibit the proliferation of CRC cells. XCT-790 treatment can also suppress the wound healing and in vitro migration of CRC cells. Cytokine assays showed that XCT-790 can significantly decrease the expression of interleukin-8 (IL-8), while not IL-4, IL-6, IL-8, IL-9, IL-10, IL-18, IFN-γ, or TGF-ß, in CRC cells. Over expression of ERRα increased the expression of IL-8. Luciferase assay showed XCT-790 decreased the promoter activity of IL-8. XCT-790 can increase the decay of IL-8 mRNA in SW480 cells. The recombinant IL-8 (rIL-8) can rescue XCT-790 induced suppression of proliferation and migration of CRC cells. XCT-790 can decrease the phosphorylation of ERK1/2 and STAT3, two downstream signal molecules of IL-8, in CRC cells. While rIL-8 can markedly attenuate XCT-790 induced dephosphorylation of ERK1/2 and STAT3. CONCLUSION: Our data showed that ERRα can trigger the proliferation and migration of CRC cells via up regulation of IL-8. Therefor targeted inhibition of ERRα/IL-8 might be a potential approach for CRC treatment and drug development.

LncRNA SSTR5-AS1 promotes esophageal carcinoma through regulating ITGB6/JAK1/STAT3 signaling.

Aim: To investigate function of somatostatin receptor 5 antisense RNA 1 (SSTR5-AS1) in esophageal carcinoma (ESCA).Materials & methods: The cellular function was assessed using EdU staining and Transwell assay. The localization of SSTR5-AS1 was measured using fluorescence in situ hybridization staining.Results: SSTR5-AS1 shRNA repressed invasion and migration and induced apoptosis in ESCA cells. SSTR5-AS1 was distributed in cytoplasm, and it regulated its subunit integrin beta 6 (ITGB6) via eukaryotic translation initiation factor 4A3 (EIF4A3). SSTR5-AS1 shRNA inactivated ITGB6 and JAK1/STAT3 signaling. SSTR5-AS1 silencing attenuated the malignant behavior of ESCA cells through the ITGB6-mediated JAK1/STAT3 axis.Conclusion: SSTR5-AS1 promotes tumorigenesis of ESCA by interacting with EIF4A3 to regulate ITGB6/JAK1/STAT3 axis, which serves a basis for discovering strategies against ESCA.

The development of esophageal carcinoma (ESCA) seriously affects the health of people. Although great efforts have been made for curing ESCA, the outcomes remain limited. In this research, we used large amounts of experiments about the molecular biology. As expected, we found knockdown of lncRNA SSTR5-AS1 could inhibit the tumorigenesis of ESCA through mediation of its subunit integrin beta 6 /JAK1/STAT3 axis. Thus, our research provided new molecular targets for ESCA treatment.

Integrative Analysis of Pyroptosis-Related Prognostic Signature and Immunological Infiltration in Lung Squamous Cell Carcinoma.

Background: Lung cancer is one of leading causes of human health threatening with approximately 2.09 million initially diagnosed cases and 1.76 million deaths worldwide annually. Pyroptosis is a programmed cell death mediated by Gasdermin family proteins. Pyroptosis could suppress the tumor oncogenesis and progression; nevertheless, pyroptosis could promote tumor growth by forming a suitable microenvironment. Methods: LASSO Cox regression analysis was performed to construct prognostic pyroptosis-related gene (PRG) signature. A ceRNA was constructed to explore the potential lncRNA-miRNA-mRNA regulatory axis in LUSC. Results: The expression of 26 PRGs were increased or decreased in LUSC. We also summarized simple nucleotide variation and copy number variation landscape of PRGs in LUSC. Prognosis analysis suggested a poor overall survival rate in LUSC patients with high expression of IL6, IL1B, ELANE, and CASP6. A pyroptosis-related prognostic signature was developed based on four prognostic PRGs. High-risk score LUSC patients had a poor overall survival rate versus low-risk score patients with an AUC of 0.565, 0.641, and 0.619 in 1-year, 3-year, and 5-year ROC curves, respectively. Moreover, the risk score was correlated with immune infiltration in LUSC. Further analysis revealed that pyroptosis-related prognostic signature was correlated with immune cell infiltration, tumor mutation burden, microsatellite instability, and drug sensitivity. We also constructed a ceRNA network and identified a lncRNA KCNQ1OT1/miR-328-3p/IL1B regulatory axis for LUSC. Conclusion: A bioinformatics method was performed to develop a pyroptosis-related prognostic signature containing four genes (IL6, IL1B, ELANE, and CASP4) in LUSC. We also constructed a ceRNA network and identified a lncRNA KCNQ1OT1/miR-328-3p/IL1B regulatory axis for LUSC. Further in vivo and in vitro studies should be conducted to verify these results.

miR-370 impacts the biological behavior of lung cancer cells by targeting the SMAD1 signaling pathway.

BACKGROUND: MicroRNAs (miRNAs) have been identified to play a role in the development and progression of lung cancer (LC). As of now, the expression and function of miR-370 in LC are still under investigation. Accordingly, this study explores the role and mechanism of miR-370 in LC. METHODS: MiR-370 mimics or inhibitors were used to transfect A549 and NCI-H460 cells to overexpress or inhibit miR-370. The colony formation test and Cell Counting Kit-8 were conducted to detect the cell proliferation activity, and transwell test and wound healing test were conducted to evaluate the cell invasion and migration activities. In addition, the downstream target genes of miR-370 in LC were verified by dual luciferase reporter assay and western blot. RESULTS: Compared to normal tissues and cell lineslines, the miR-370 expression in LC tissues and cells was decreased greatly. Compared to the negative control group, the up-regulation of miR-370 greatly intensified the apoptosis of NCI-H460 cells and weakened the migration, proliferation, and invasion of the cells. However, compared to the inhibitor-negative control group, the downregulation of miR-370 caused the opposite results. Additionally, SMAD family member 1 (SMAD1) was identified as a direct target of miR-370 in LC and could be inhibited by miR-370. Its overexpression restored the impact of miR-370 mimics on LC cells. CONCLUSION: With low expression in LC tissues and cell lineslines, miR-370 is a tumor suppressor that weakens the growth, invasion as well as migration of LC cells by inhibiting SMAD1 expression. Our results may provide novel insights for the biological treatment of LC.

HDAC1 regulates the chemosensitivity of laryngeal carcinoma cells via modulation of interleukin-8 expression.

Chemotherapies such as 5-fluorouracil (5-FU) and cisplatin (CDDP) have been widely used to treat laryngeal squamous cell carcinoma (LSCC), the second most common head and neck squamous cell carcinoma. However, chemoresistance seriously impairs chemotherapeutic efficacy. Our present study reveals that 5-FU and CDDP treatment increase the expression of histone deacetylase 1 (HDAC1) in LSCC cells. Consistently, increased levels of HDAC1 are observed in chemoresistant cells. Knockdown of HDAC1 significantly restores the sensitivity of LSCC cells, as HDAC1 increases the expression of interleukin-8 (IL-8), which is essential for LSCC chemoresistance. Mechanistically, HDAC1 directly initiates the transcription of IL-8 though binding to its promoter. Simultaneously, si-HDAC1 increases the levels of miR-93, which binds to the 3'UTR of IL-8 mRNA to trigger its degradation. In summary, the HDAC1/IL-8 axis can confer chemotherapeutic resistance to LSCC cells.

Valproic acid promotes the epithelial-to-mesenchymal transition of breast cancer cells through stabilization of Snail and transcriptional upregulation of Zeb1.

Histone deacetylases (HDACs) can regulate cancer progression and its inhibitors (HDACIs) have been widely used for cancer therapy. Valproic acid (VPA, 2-propylpentanoic acid) can inhibit the class I HDAC and suppress the malignancy of solid cancers. Our present study revealed that 1 mM VPA, which has no effect on cell proliferation, can significantly increase the migration and induce epithelial to mesenchymal transition (EMT) like properties of breast cancer cells. Further, VPA increased the expression of EMT-transcription factors (EMT-TFs) Snail and Zeb1. Knockdown of Snail and Zeb1 can attenuate VPA induced cell migration and EMT. Mechanistically, VPA increased the protein stability of Snail via suppression its phosphorylation at Ser 11. As to Zeb1, VPA can increase its promoter activity and transcription via a HDAC2 dependent manner. Over expression of HDAC2 can block VPA induced expression of Zeb1. Collectively, our data revealed that VPA can trigger the EMT of breast cancer cells via upregulation of Snail and Zeb1. It indicated that more attention should be paid to the effects of VPA on the clinical therapy of breast cancer.