ITGB1 Expression Research Articles

Hsa-miR-183-5p Modulates Cell Adhesion by Repression of ITGB1 Expression in Prostate Cancer.

Prostate cancer is a major health problem worldwide. MiR-183 is an oncomiR and a candidate biomarker in prostate cancer, affecting various pathways responsible for disease initiation and progression. We sought to discover the most relevant processes controlled by miR-183 through an unbiased transcriptomic approach using prostate cell lines and patient tissues to identify miR-183 responsive genes and pathways. Gain of function experiments, reporter gene assays, and transcript and protein measurements were conducted to validate predicted functional effects and protein mediators. A total of 135 candidate miR-183 target genes overrepresenting cell adhesion terms were inferred from the integrated transcriptomic analysis. Cell attachment, spreading assays and focal adhesion quantification of miR-183-overexpressing cells confirmed the predicted reduction in cell adhesion. ITGB1 was validated as a major target of repression by miR-183 as well as a mediator of cell adhesion in response to miR-183. The reporter gene assay and PAR-CLIP read mapping suggest that ITGB1 may be a direct target of miR-183. The negative correlation between miR-183 and ITGB1 expression in prostate cancer cohorts supports their interaction in the clinical set. Overall, cell adhesion was uncovered as a major pathway controlled by miR-183 in prostate cancer, and ITGB1 was identified as a relevant mediator of this effect.

Royal Jelly Extract Accelerates Keratinocyte Proliferation, and Upregulates Laminin <i>α</i>3 and Integrin <i>β</i>1 mRNA Expression, via Akt/mTOR/HIF-1<i>α</i> Pathway

Background: In the previous decade, various benefits and biological activities of royal jelly, applied in alternative and modern medicine, and cosmetics, have been reported. However, the effects of royal jelly extract (RJ) on keratinocytes have not been fully elucidated. Objective: The primary objectives of this study were to reveal the effects of RJ on keratinocytes and explore the underlying mechanism. Methods: HaCaT cells, an immortal human epidermis-derived keratinocyte cell line, were used in this study. Laminin α3 (LAMA3), integrin β1 (ITGB1), and hypoxia-inducible factor-1α (HIF-1α) mRNA expression levels were determined using real-time PCR. Cell proliferation rate was measured using a bromodeoxyuridine uptake assay. Results: RJ treatment upregulated LAMA3, ITGB1 and HIF-1α mRNA expression, and accelerated HaCaT cell proliferation. Akt and mTOR inhibitors suppressed the RJ-induced HIF-1α expression and cell proliferation. HIF-1α silencing abrogated RJ-induced LAMA3 and ITGB1 mRNA expression and cell proliferation, whereas LAMA3 silencing and antibody-mediated ITGB1 blockade did not affect the effects of RJ. Conclusion: RJ upregulates LAMA3 and ITGB1 mRNA expression levels by HIF-1α expression enhancement. In addition, RJ accelerates keratinocyte proliferation via Akt/mTOR/HIF-1α/NF-κB signaling pathway. These suggest that RJ is beneficial for anti-aging, as a skin care product ingredient.

ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells.

Respiratory syncytial virus (RSV) infection is the main cause of bronchiolitis in children. Excessive mucus secretion is one of the primary symbols in RSV related lower respiratory tract infections (RSV-related LRTI), which is closely associated with the occurrence and development of asthma in later life. Integrin β4 (ITGB4) is down-regulated in the airway epithelial cells (AECs) of asthma patients which plays a critical role in the pathogenesis of asthma. However, whether ITGB4 is involved in the pathological processes of RSV infection remains unclear. In this study, we found that decreased expression of ITGB4 was negatively correlated with the level of MUC5AC in childhood AECs following RSV infection. Moreover, ITGB4 deficiency led to mucus hypersecretion and MUC5AC overexpression in the small airway of RSV-infected mice. MUC5AC expression was upregulated by ITGB4 in HBE cells through EGFR, ERK and c-Jun pathways. EGFR inhibitors treatment inhibited mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection. Together, these results demonstrated that epithelial ITGB4 deficiency induces mucus hypersecretion by upregulating the expression of MUC5AC through EGFR/ERK/c-Jun pathway, which further associated with RSV-related LRTI.

Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant metastasis of nasopharyngeal carcinoma by upregulating ITGB3.

Nasopharyngeal carcinoma (NPC) is a malignancy with high metastatic and invasive nature. Distant metastasis contributes substantially to treatment failure and mortality in NPC. Platelets are versatile blood cells and the number of platelets is positively associated with the distant metastasis of tumor cells. However, the role and underlying mechanism of platelets responsible for the metastasis of NPC cells remain unclear. Here we found that the distant metastasis of NPC patients was positively correlated with the expression levels of integrin β3 (ITGB3) in platelet-derived extracellular vesicles (EVs) from NPC patients (P-EVs). We further revealed that EVs transfer occurred from platelets to NPC cells, mediating cell-cell communication and inducing the metastasis of NPC cells by upregulating ITGB3 expression. Mechanistically, P-EVs-upregulated ITGB3 increased SLC7A11 expression by enhancing protein stability and activating the MAPK/ERK/ATF4/Nrf2 axis, which suppressed ferroptosis, thereby facilitating the metastasis of NPC cells. NPC xenografts in mouse models further confirmed that P-EVs inhibited the ferroptosis of circulating NPC cells and promoted the distant metastasis of NPC cells. Thus, these findings elucidate a novel role of platelet-derived EVs in NPC metastasis, which not only improves our understanding of platelet-mediated tumor distant metastasis, but also has important implications in diagnosis and treatment of NPC.

ITGB1 Drives Hepatocellular Carcinoma Progression by Modulating Cell Cycle Process Through PXN/YWHAZ/AKT Pathways.

Integrin β1 (ITGB1), which acts as an extracellular matrix (ECM) receptor, has gained increasing attention as a therapeutic target for the treatment of hepatocellular carcinoma (HCC). However, the underpinning mechanism of how ITGB1 drives HCC progression remains elusive. In this study, we first found that ITGB1 expression was significantly higher in HCC tissues than in normal controls by bioinformatics analysis. Furthermore, bioinformatics analysis revealed that paxillin (PXN) and 14-3-3 protein zeta (YWHAZ) are the molecules participating in ITGB1-regulated HCC tumor cell cycle progression. Indeed, immunohistochemistry (IHC) revealed that ITGB1, paxillin, and YWHAZ were strongly upregulated in paired HCC tissue compared with adjacent normal tissues. Notably, the inhibition of ITGB1 expression by small interfering RNA (siRNA) resulted in the downregulated expression of PXN and YWHAZ in primary HCC cells, as assessed by western blot and immunostaining. In addition, ITGB1 knockdown markedly impaired the aggressive behavior of HCC tumor cells and delayed cell cycle progression as determined by cell migration assay, drug-resistance analysis, colony formation assay, quantitative real-time polymerase chain reaction (qRT-PCR), and cell cycle analysis as well as cell viability measurements. More importantly, we proved that xenograft ITGB1high tumors grew more rapidly than ITGB1low tumors. Altogether, our study showed that the ITGB1/PXN/YWHAZ/protein kinase B (AKT) axis enhances HCC progression by accelerating the cell cycle process, which offers a promising approach to halt HCC tumor growth.

Knockdown of CCL28 inhibits endometriosis stromal cell proliferation and invasion via ERK signaling pathway inactivation.

Endometriosis (EM), the presence of functional endometrial glands and stroma outside the uterine cavity, is a common gynecological disorder. At present, the pathogenesis of EM has not been fully elucidated, so there is still a lack of effective therapy. The present study aimed to explore the role of C-C motif chemokine ligand 28 (CCL28) and its underlying mechanism in endometrial stromal cells to propose a novel therapy for EM treatment. The expression of CCL28 and CC chemokine receptor 10 (CCR10) were examined. After CCL28 knockdown or overexpression by lentivirus infection, cell proliferation and invasion were measured. It was revealed that compared with normal, the expression levels of CCL28 and CCR10 were significantly elevated in endometrial tissues of patients with EM. Knockdown of CCL28 in endometrial stromal cells significantly suppressed cell proliferation and invasion, and this was accompanied by significantly reduced expression levels of CCR10, MMP2, MMP9, integrin β1 (ITGB1) and phosphorylated (p)-ERK/ERK ratio. The addition of the CCL28 recombinant protein had an opposite effect to CCL28 downregulation. Furthermore, the ERK inhibitor, PD98059, reduced CCL28-induced cell proliferation and invasion, as well as the expression levels of MMP2, MMP9, ITGB1 and p-ERK. Therefore, the present study indicated that CCL28 may contribute to the progression of EM by regulating MMP2, MMP9 and ITGB1 expression and function via the activation of the ERK signaling pathway.

Aldehyde dehydrogenase 3B2 promotes the proliferation and invasion of cholangiocarcinoma by increasing Integrin Beta 1 expression

Aldehyde dehydrogenases (ALDHs) play an essential role in regulating malignant tumor progression; however, their role in cholangiocarcinoma (CCA) has not been elucidated. We analyzed the expression of ALDHs in 8 paired tumor and peritumor perihilar cholangiocarcinoma (pCCA) tissues and found that ALDH3B1 and ALDH3B2 were upregulated in tumor tissues. Further survival analysis in intrahepatic cholangiocarcinoma (iCCA, n = 27), pCCA (n = 87) and distal cholangiocarcinoma (dCCA, n = 80) cohorts have revealed that ALDH3B2 was a prognostic factor of CCA and was an independent prognostic factor of iCCA and pCCA. ALDH3B2 expression was associated with serum CEA in iCCA and dCCA, associated with tumor T stage, M stage, neural invasion and serum CA19-9 in pCCA. In two cholangiocarcinoma cell lines, overexpression of ALDH3B2 promoted cell proliferation and clone formation by promoting the G1/S phase transition. Knockdown of ALDH3B2 inhibited cell migration, invasion, and EMT in vitro, and restrained tumor metastasis in vivo. Patients with high expression of ALDH3B2 also have high expression of ITGB1 in iCCA, pCCA, and dCCA at both mRNA and protein levels. Knockdown of ALDH3B2 downregulated the expression of ITGB1 and inhibited the phosphorylation level of c-Jun, p38, and ERK. Meanwhile, knockdown of ITGB1 inhibited the promoting effect of ALDH3B2 overexpression on cell proliferation, migration, and invasion. ITGB1 is also a prognostic factor of iCCA, pCCA, and dCCA and double-positive expression of ITGB1 and ALDH3B2 exhibits better performance in predicting patient prognosis. In conclusion, ALDH3B2 promotes tumor proliferation and metastasis in CCA by regulating the expression of ITGB1 and upregulating its downstream signaling pathway. The double-positive expression of ITGB1 and ALDH3B2 serves as a better prognostic biomarker of CCA.

P.0061 Ketamine affects expression of Itgb3, Itgav, Chl1 and Sirt1 in the prefrontal cortex of rats in a depressive-like behaviour model

P.0061 Ketamine affects expression of Itgb3, Itgav, Chl1 and Sirt1 in the prefrontal cortex of rats in a depressive-like behaviour model

Integrin β3 Induction Promotes Tubular Cell Senescence and Kidney Fibrosis.

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin β3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-β, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

Integrin-β6 Serves as a Potential Prognostic Serum Biomarker for Gastric Cancer.

Discovering novel biomarkers that easily accessed is a key step towards the personalized medicine approach for gastric cancer patients. Integrin-β6 (ITGB6) is a subtype of integrin that is exclusively expressed on the surface of epithelial cells and is up-regulated in various tumors. In the present study, a retrospective cohort with 135 gastric cancer patients and a prospective cohort with 34 gastric cancer patients were constructed, ITGB6 expression were detected in both the serum specimens and the tissue specimens. Detailed clinicopathological parameters as well as patients’ survival were recorded. A nomogram including ITGB6 expression was also constructed and validated to predict the prognosis of gastric cancer patients. Results showed that serum ITGB6 expression was obviously increased and associated with tumor stage in gastric cancer patients, serum ITGB6 expression was relatively high in patients with liver metastasis. High ITGB6 expression indicated a poor prognosis, and nomogram including serum ITGB6 expression could predict the prognosis of gastric cancer patients effectively. Moreover, serum ITGB6 expression was associated with ITGB6 expression in tumor tissues. Furthermore, combined serum ITGB6 and CEA levels contributed to the risk stratification and prognostic prediction for gastric cancer patients. In addition, the serum expression of ITGB6 decreased significantly after radical surgery, and a new rise in serum ITGB6 expression indicated tumor recurrence or progression. The present study identified a novel serum biomarker for the risk stratification, prognostic prediction and surveillance of gastric cancer patients.

LncRNA LINC00115 facilitates lung cancer progression through miR-607/ITGB1 pathway.

Dysregulated long noncoding RNAs (lncRNAs) have potential roles in various cancer types. The objective of this study was to investigate the expression and the underlying role of long intergenic nonprotein coding RNA 115 (LINC00115) in lung cancer. The relative expression of LINC00115 and miR-607 in tumor tissues and cells was detected by real-time PCR. After overexpression or knockdown of LINC00115 expression in tumor cells, the changes in the proliferation, migration, and invasion capacities were detected via Counting Kit-8 (CCK-8) assay and transwell assays. The interplay among LINC00115, miR-607, and integrin β1 (ITGB1) was confirmed by bioinformatics analyses and luciferase reporter assay. In addition, tumor cells with LINC00115 knockdown were injected into nude mice to investigate the effect of LINC00115 on tumorigenesis in vivo. LINC00115 was highly expressed in tumor tissues and cells. LINC00115 promoted the malignant properties of tumor cells. Investigation to its molecular mechanism revealed that LINC00115 functioned as a competitive endogenous RNA (ceRNA), regulating the expression of ITGB1 by sponging miR-607 to affect tumor growth. The LINC00115/miR-607/ITGB1 signaling axis might be a novel therapeutic target in lung cancer.

LncRNA SOCS2-AS1 promotes the progression of glioma via regulating ITGB1 expression

BackgroundAccumulating evidence has underscored the important role of long non-coding RNAs (lncRNAs) in the development and progression of glioma. However, the role of lncRNA SOCS2-AS1 in glioma is largely unknown. MethodslncRNA SOCS2-AS1 silencing was achieved by specific siRNAs. Proliferation of glioma cell line after lncRNA SOCS2-AS1 silencing was examined by MTT assay, Transwell assay was used to confirm changes of invasion and migration of glioma cells, and study the molecular mechanism of lncRNA SOCS2-AS1 by RT-qPCR and bioinformatics analysis. ResultsWe identified that lncRNA SOCS2-AS1 was significantly upregulated in glioma, and its overexpression was closely related with malignant clinical features and poor prognosis. To explore the cellular function of SOCS2-AS1, we performed loss-of function assays in two glioma cells. We demonstrated that SOCS2-AS1 knockdown repressed glioma cell proliferation, migration and invasion. Mechanistically, SOCS2-AS1 expression was positively correlated with the expression levels of core factors ITGB1 of ECM-receptor interaction signaling pathway in glioma. Moreover, SOCS2-AS1 knockdown suppressed ITGB1 expression in glioma cells. Finally, rescue assays were carried out to determine that ITGB1 involved in SOCS2-AS1-mediated glioma cell proliferation, migration and invasion. ConclusionOur findings provided the first evidence suggested that SOCS2-AS1 promoted the progression of glioma via upregulating ITGB1 expression.

ITGB4 as a novel serum diagnosis biomarker and potential therapeutic target for colorectal cancer.

PurposeTo develop new and effective biomarkers for the diagnosis of colorectal cancer (CRC).Experimental designThe serum expression of ITGB4 (49 CRC and 367 HC) was detected by enzyme‐linked immunosorbent assay (ELISA), and its diagnostic value was analyzed using the receiver operating characteristic (ROC) curve. The sensitivity and specificity of ITGB4 in CRC diagnosis were calculated through statistical analysis. The optimal clinical cutoff value was calculated using the Youden index, and diagnostic efficacy was analyzed in a larger serum sample (98 CRC and 1631 non‐CRC). The expression of ITGB4 was measured by CyTOF (cell experimental technology) at the single‐cell level, and characteristics were analyzed using viSNE and SPADE TREE.ResultsSerum ITGB4 and CEA levels were significantly higher in CRC patients than in HC and non‐CRC patients. The use of serum ITGB4 levels for the diagnosis of CRC has a high sensitivity (79%) but not high specificity when the clinical cutoff value was 0.70 ng/mL. However, the optimal cutoff value was 1.6 ng/mL with 86.2% specificity and 52.0% sensitivity, and the diagnostic efficacy was greatly improved with high specificity (82.0%) and sensitivity (71.4%) when combined with CEA. ITGB4 expression characteristics were measured and related to the expression of EpCAM, Ck8/18, and perforin at the single‐cell level. Single‐cell analysis showed that cell clusters with low expression of CK8/18 and ITGB4 were more sensitive to 5FU and radiotherapy (RT).ConclusionsITGB4 is an effective diagnostic serum biomarker and a potential therapeutic target for CRC.

LncRNA ITGB8-AS1 functions as a ceRNA to promote colorectal cancer growth and migration through integrin-mediated focal adhesion signaling

Long non-coding RNAs (lncRNAs) play critical roles in tumorigenesis and progression of colorectal cancer (CRC). However, functions of most lncRNAs in CRC and their molecular mechanisms remain uncharacterized. Here we found that lncRNA ITGB8-AS1 was highly expressed in CRC. Knockdown of ITGB8-AS1 suppressed cell proliferation, colony formation, and tumor growth in CRC, suggesting oncogenic roles of ITGB8-AS1. Transcriptomic analysis followed by KEGG analysis revealed that focal adhesion signaling was the most significantly enriched pathway for genes positively regulated by ITGB8-AS1. Consistently, knockdown of ITGB8-AS1 attenuated the phosphorylation of SRC, ERK, and p38 MAPK. Mechanistically, ITGB8-AS1 could sponge miR-33b-5p and let-7c-5p/let-7d-5p to regulate the expression of integrin family genes ITGA3 and ITGB3, respectively, in the cytosol of cells. Targeting ITGB8-AS1 using antisense oligonucleotide (ASO) markedly reduced cell proliferation and tumor growth in CRC, indicating the therapeutic potential of ITGB8-AS1 in CRC. Furthermore, ITGB8-AS1 was easily detected in plasma of CRC patients, which was positively correlated with differentiation and TNM stage, as well as plasma levels of ITGA3 and ITGB3. In conclusion, ITGB8-AS1 functions as a competing endogenous RNA (ceRNA) to regulate cell proliferation and tumor growth of CRC via regulating focal adhesion signaling. Targeting ITGB8-AS1 is effective in suppressing CRC cell growth and tumor growth. Elevated plasma levels of ITGB8-AS1 were detected in advanced-stage CRC. Thus, ITGB8-AS1 could serve as a potential therapeutic target and circulating biomarker in CRC.

β6-Integrin Serves as a Potential Serum Marker for Diagnosis and Prognosis of Pancreatic Adenocarcinoma.

INTRODUCTION:Despite enormous efforts during the past decades, pancreatic adenocarcinoma (PAC) remains one of the most deleterious cancer entities. A useful biomarker for early detection or prognosis of PAC does not yet exist. The goal of our study was the characterization of β6-integrin (ITGB6) as a novel serum tumor marker for refined diagnosis and prognosis of PAC. Serum ITGB6 levels were analyzed in 3 independent PAC cohorts consisting of retrospectively and prospectively collected serum and/or (metastatic) PAC tissue specimens.METHODS:Using 2 independent cohorts, we measured serum ITGB6 concentrations in 10 chronic pancreatitis patients, 10 controls, as well as in 27 (cohort 1) and 24 (cohort 2) patients with PAC, respectively. In these patients, we investigated whether ITGB6 serum levels correlate with known clinical and prognostic markers for PAC and whether they might differ between patients with PAC or benign inflammatory diseases of the pancreas.RESULTS:We found that elevated serum ITGB6 levels (≥0.100 ng/mL) in patients suffering from metastasizing PAC presented an unfavorable prognostic outcome. By correlating the ITGB6 tissue expression in primary and metastatic PAC with clinical parameters, we found that positive ITGB6 expression in the tumor tissue is linked to increased serum ITGB6 levels in nonmetastatic PAC and correlates with carbohydrate antigen 19-9 and clinical outcome.DISCUSSION:Our findings suggest that ITGB6 might serve as a novel serum biomarker for early diagnosis and prognosis of PAC. Given the limited specificity and sensitivity of currently used carbohydrate antigen 19-9–based assays, ITGB6 may have the potential to improve the diagnostic accuracy for PAC.

Combined bioinformatics technology to explore pivot genes and related clinical prognosis in the development of gastric cancer

To screen the key genes in the development of gastric cancer and their influence on prognosis. The GEO database was used to screen gastric cancer-related gene chips as a training set, and the R packages limma tool was used to analyze the differential genes expressed in gastric cancer tissues compared to normal tissues, and then the selected genes were verified in the validation set. The String database was used to calculate their Protein–protein interaction (PPI) network, using Cytoscape software's Centiscape and other plug-ins to analyze key genes in the PPI network. The DAVID database was used to enrich and annotate gene functions of differential genes and PPI key module genes, and further explore correlation between expression level and clinical stage and prognosis. Based on clinical data and patient samples, differential expression of key node genes was verified by immunohistochemistry. The 63 characteristic differential genes screened had good discrimination between gastric cancer and normal tissues, and are mainly involved in regulating extracellular matrix receptor interactions and the PI3k-AKT signaling pathway. Key nodes in the PPI network regulate tumor proliferation and metastasis. Analysis of the expression levels of key node genes found that relative to normal tissues, the expression of ITGB1 and COL1A2 was significantly increased in gastric cancer tissues, and patients with late clinical stages of tumors had higher expression of ITGB1 and COL1A2 in tumor tissues, and their survival time was longer (P < 0.05). This study found that ITGB1 and COL1A2 are key genes in the development of gastric cancer and can be used as prognostic markers and potential new targets for gastric cancer.

ITGB1 Enhances the Proliferation, Survival, and Motility in Gastric Cancer Cells

ITGB1 (Integrin β1, CD29) is a member of the integrin family and has a role as a major adhesion receptor. Gastric cancer (GC) is an important cause of mortality worldwide, especially in China. As a potential cancer enhancer, the role ITGB1 plays in GC progression remains unclear. In the current study, our assay on the databases of tumoassociated gene expression and interaction found that the high expression of ITGB1 was closely correlated with the poor prognosis of GC patients. To explore the roles, ITGB1 plays in GC progression, and an ITGB1-deleted cell line (ITGB1−/−SGC7901) was generated using the CRISPR/Cas9 method. The tumor malignancy-associated cell behaviors and microstructures were detected, imaged, and analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, scanning electron microscopy, laser scanning confocal microscopy, and others. The results indicated that ITGB1 deletion decreased the GC cell proliferation and motility, and inhibited motility-relevant microstructures, such as pseudopodia and filopodia, markedly in ITGB1-deleted SGC7901 cells. The analysis of STRING database and western blots indicated that ITGB1 contributes to the malignancy of GC mediated by Src-mediated FAK/PI3K/Akt signaling pathways. Taken together, the results showed that ITGB1 may be a potential targeting marker for GC diagnosis and therapy in the future.

N6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1.

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

Rac1-mediated sustained β4 integrin level develops reattachment ability of breast cancer cells after anchorage loss.

Previously, we reported that non‐apoptotic cell death was induced in non‐malignant mammary epithelial cells (HMECs) upon loss of anchorage during 48 h incubation in suspension. In this study, we examined HMECs in suspension at an earlier time point and found that most of them lost attachment ability to substrata when replated, although >80% were alive. This suggested that HMECs lost reattachment ability (RA) prior to cell death upon detachment. Concomitant with the loss of RA, a decrease in the levels of β1 and β4 integrin was observed. In sharp contrast, breast cancer cells retained integrin levels, reattached to substrata, and formed colonies after exposure to anchorage loss as efficiently as those maintained under adherent conditions. Such RA of cancer cells is essential for the metastatic process, especially for establishing adhesion contact with ECM in the secondary organ after systemic circulation. Further analysis suggested that sustained levels of β4 integrin, which was mediated by Rac1, was critical for RA after anchorage loss and lung metastasis of breast cancer cells. In the cancer cells, persistent Rac1 activity enhanced escape of β4 integrin from lysosomal degradation depending on actin‐related protein 2/3 and TBC1D2, a GTPase‐activating protein of Rab7 GTPase. Notably, simultaneous high expression of ITGB4 and RAC1 was associated with poor prognosis in patients with breast cancer. Therefore, β4 integrin and Rac1 are attractive therapeutic targets to eliminate RA in cancer cells, thereby preventing the initial step of colonization at the secondary organ during metastasis.

Long non-coding RNA Lnc-408 promotes invasion and metastasis of breast cancer cell by regulating LIMK1

Invasion and metastasis are the leading causes of death in patients with breast cancer (BC), and epithelial-mesenchymal transformation (EMT) plays an essential role in this process. Here, we found that Lnc-408, a novel long noncoding RNA (lncRNA), is significantly upregulated in BC cells undergoing EMT and in BC tumor with lymphatic metastases compared with those without lymphatic metastases. Lnc-408 can enhance BC invasion and metastasis by regulating the expression of LIMK1. Mechanistically, Lnc-408 serves as a sponge for miR-654-5p to relieve the suppression of miR-654-5p on its target LIMK1. Knockdown or knockout of Lnc-408 in invasive BC cells clearly decreased LIMK1 levels, and ectopic Lnc-408 in MCF-7 cells increased LIMK1 expression to promote cell invasion. Lnc-408-mediated enhancement of LIMK1 plays a key role in cytoskeletal stability and promotes invadopodium formation in BC cells via p-cofilin/F-actin. In addition, the increased LIMK1 also facilitates the expression of MMP2, ITGB1, and COL1A1 by phosphorylating CREB. In conclusion, our findings reveal that Lnc-408 promotes BC invasion and metastasis via the Lnc-408/miR-654-5p/LIMK1 axis, highlighting a novel promising target for the diagnosis and treatment of BC.