Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αβ1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin β1. In its absence, generation of full length β1 was reduced, immature β1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3\'s role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.

In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical squamous cell carcinoma in China have increased significantly. The screening and identification of reliable biomarkers and candidate drug targets for cervical squamous cell carcinoma are urgently needed to improve the survival rate and quality of life of patients. In this study, we demonstrated that the expression of MUC1 was greater in neoplastic tissues than in non-neoplastic tissues of the cervix, and cervical squamous cell carcinoma patients with high MUC1 expression had significantly worse overall survival than did those with low MUC1 expression, indicating its potential for early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in cervical squamous cell carcinoma. MUC1 could upregulate ITGA2 and ITGA3 expression via ERK phosphorylation, promoting the proliferation and metastasis of cervical cancer cells. Further knockdown of ITGA2 and ITGA3 significantly inhibited the tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen comprising MUC1-siRNA and a novel ERK inhibitor in vivo and found that the combination of these drugs achieved better results in animals with xenografts than did MUC1 alone. Overall, we discovered a novel regulatory pathway, MUC1/ERK/ITGA2/3, in cervical squamous cell carcinoma that may serve as a potential biomarker and therapeutic target in the future.
MUC1 is overexpressed in cervical squamous cell carcinoma. MUC1 regulates ERK phosphorylation, and subsequently upregulates ITGA2 and ITGA3 expression to promote tumorigenesis in cervical squamous cell carcinoma. A combination drug regimen targeting MUC1 and ERK achieved better results compared than MUC1 alone.

m6A demethylase FTO is confirmed to be involved in pancreatic cancer progression. FTO regulates miRNA processing. To investigate the regulatory effect of FTO on miR-383-5p and its role in pancreatic cancer. The expression of miR-383-5p, ITGA3, and FTO was predicted using bioinformatic analysis in tissues and was measured using qPCR in cells. Cell biological functions were investigated using MTT assay, Transwell assay, sphere formation assay, and qPCR. The targeting relationship between miR-383-5p and ITGA3 was evaluated using the dual-luciferase reporter assay. The effect of FTO on miR-383-5p processing was evaluated using RIP and MeRIP assay. FTO expression was upregulated in pancreatic cancer and silencing of FTO promoted the processing of miR-383-5p in an m6A-dependent manner. m6A-modified miRNA processing was recognized by IGF2BP1. Downregulation of miR-383-5p reversed FTO knockdown-induced inhibition of cellular processes. The FTO/miR-383-5p/ITGA3 axis facilitated cell viability, metastasis, and stemness in pancreatic cancer.

Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy in post-stroke motor recovery. However, the underlying mechanisms of rTMS regulates long-lasting changes with synaptic transmission and glutamate receptors function (including AMPARs or NMDARs) remains unclear.
Mice were received 10-Hz rTMS treatment once daily on the third day after photothrombotic (PT) stroke for 18 days. Motor behaviors and the Western blot were used to evaluate the therapeutic efficacy of 10-Hz rTMS in the mice with PT model. Moreover, we used wild-type (WT) and NEX-α3-/- mice to further explore the 10-Hz rTMS effect.
We found that 10-Hz rTMS improved the post-stroke motor performance in the PT mice. Moreover, the levels of AMPAR, vGlut1, and integrin α3 in the peri-infarct were significantly increased in the rTMS group. In contrast, 10-Hz rTMS did not induce these aforementioned effects in NEX-α3-/- mice. The amplitude of AMPAR-mediated miniature excitatory postsynaptic currents (EPSCs) and evoked EPSCs was increased in the WT + rTMS group, but did not change in NEX-α3-/- mice with rTMS.
In this study, 10-Hz rTMS improved the glutamatergic synaptic transmission in the peri-infract cortex through effects on integrin α3 and AMPARs, which resulted in motor function recovery after stroke.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including TH17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic TH17 cell migration. Here, we report integrin α3 as a TH17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis. CNS-infiltrating TH17 cells express high integrin α3, and its deletion in CD4+ T cells or Il17a fate-mapped cells attenuated disease severity. Mechanistically, integrin α3 enhanced the immunological synapse formation to promote the polarization and proliferation of TH17 cells. Moreover, the transmigration of TH17 cells into the CNS was dependent on integrin α3, and integrin α3 deficiency enhanced the retention of CD4+ T cells in the perivascular space of the blood-brain barrier. Integrin α3-dependent interactions continuously maintain TH17 cell identity and effector function. The requirement of integrin α3 in TH17 cell pathogenicity suggests integrin α3 as a therapeutic target for MS treatment.

Contribution of integrin superfamily genes to treatment resistance remains uncertain. Genome patterns of thirty integrin superfamily genes were analyzed of using bulk and single-cell RNA sequencing, mutation, copy number, methylation, clinical information, immune cell infiltration, and drug sensitivity data. To select the integrins that are most strongly associated with treatment resistance in pancreatic cancer, a purity-independent RNA regulation network including integrins were constructed using machine learning. The integrin superfamily genes exhibit extensive dysregulated expression, genome alterations, epigenetic modifications, immune cell infiltration, and drug sensitivity, as evidenced by multi-omics data. However, their heterogeneity varies among different cancers. After constructing a three-gene (TMEM80, EIF4EBP1, and ITGA3) purity-independent Cox regression model using machine learning, ITGA3 was identified as a critical integrin subunit gene in pancreatic cancer. ITGA3 is involved in the molecular transformation from the classical to the basal subtype in pancreatic cancer. Elevated ITGA3 expression correlated with a malignant phenotype characterized by higher PD-L1 expression and reduced CD8+ T cell infiltration, resulting in unfavorable outcomes in patients receiving either chemotherapy or immunotherapy. Our findings suggest that ITGA3 is an important integrin in pancreatic cancer, contributing to chemotherapy resistance and immune checkpoint blockade therapy resistance.

BACKGROUND: Glycans are strongly involved in stability and function of integrins (ITG) and tetraspanin protein CD63 and their respective interaction partners as they are dysregulated in the tumorigenic processes. Glycosylation changes is a universal phenomenon of cancer cells. In this study, glycosylation changes in epithelial ovarian cancer (EOC) are explored using tetraspanin and integrin molecules.
METHODS: ITG and CD63 were immobilized from 10 EOC and 5 benign ovarian cyst fluid on microtiter wells and traced with 3 glycan binding proteins (STn, WGA, UEA) conjugated on europium nanoparticles. Total protein measurements (ITG & CD63 immunoassays) were also performed. The most promising glycovariant candidates identified were then clinically evaluated on the whole cohort of 77 ovarian cyst fluids. Additional testing was performed in ascites fluid samples of liver cirrhosis (n = 2) and EOC (n = 4).
RESULTS: Sialylated Tn antibody based glycovariants of ITGα3 (ITGα3STn) and CD63 (CD63STn) performed better than corresponding protein epitope-based immunoassays, ITGα3IA and CD63IA respectively. Combined ITGα3 based assays (ITGα3IA + ITGα3STn) detected 49 out of 55 malignant & borderline cases without detecting any of the 22 benign and healthy cysts.
CONCLUSIONS: Our findings indicate the potential diagnostic application of ITGα3STn along with total ITGα3IA, which could help reduce the unnecessary surgeries. The results encourage studying further the potential use of these novel assays to detect EOC at earlier clinical stages.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor. Integrins have been implicated in the malignancy of GBM. A recent study demonstrated that integrin α3 (ITGA3) promoted the invasion of breast cancer cells by regulating transcriptional factor POU3F2. However, whether this also happened in GBM remained unknown.
METHODS: Therefore, we explored the relationship between ITGA3 and POU3F2 in GBM. We measured the expression of ITGA3 and POU3F2 in GBM tissues. We generated ITGA3 knockdown and POU3F2 knockdown GBM U87MG cells and the proliferation, migration and invasion, the expression of stemness markers and epithelial to mesenchymal transition (EMT) markers were measured. We transplanted ITGA3 knockdown and POU3F2 knockdown GBM U87MG cells into mice. The mice were treated with anti-ITGA3 antibody. The tumor sizes, the expression of stemness markers and epithelial-to-mesenchymal transition (EMT) markers were measured.
RESULTS: Both ITGA3 and POU3F2 were upregulated in GBM tissues. Knocking down ITGA3 resulted in reduced expression of POU3F2. Knocking down ITGA3 and POU3F2 suppressed U87MG cells proliferation, migration and invasion, inhibited the expression of stemness markers and prevented epithelial- to-mesenchymal transition. The transplantation of ITGA3 knockdown and POU3F2 knockdown U87MG cells decreased tumor size.
CONCLUSIONS: Anti-ITGA3 antibody treatment reduced the tumor size. ITGA3 regulates stemness and invasion of glioblastoma through POU3F2.

Recurrent spontaneous abortion (RSA) is a disturbing pregnancy disorder experienced by ~2.5% of women attempting to conceive. The pathogenesis of RSA is still unclear. Previous findings revealed that transcription factor YIN-YANG 1(YY1) was related to the pathogenesis of RSA by influence trophoblastic cell invasion ability. Present study aimed to investigate more specific molecular mechanism of YY1 playing in trophoblastic cells. In our research, RNA-seq and Chip-seq were used to find significant changed genes between si-YY1(Knock down of YY1) HTR-8/SVneo cells(n = 3) and HTR-8/SVneo cells(n = 3). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results suggested that Integrins related pathway maybe necessary to biological functions of trophoblastic cells. Chip-seq dataset analysis results predict YY1 can regulate ITGA3/7 expression by binding to the promoter region of ITGA3/7. Furthermore, results from chip experiment, RT-PCR, Dual-luciferase reporter gene assay showed that YY1 was able to bind to the promoter region of ITGA3 and regulate ITGA3 mRNA and protein expression. However, ITGA7 could not be significant influenced by YY1. Besides, gene silencing experiment, Western blot and Immunofluorescence assay confirmed that both YY1 and ITGA3 can accelerate phosphorylation focal adhesion kinase and affect cytoskeleton formation in HTR-8/SVneo cells. In conclusion, YY1/ITGA3 play a critical role in trophoblast invasion ability by regulating cytoskeleton formation.

As a kind of recognition molecule, aptamers can be inserted into some regulatory sequences for the smart response of their targets. However, the molecular engineering might lead to the change of the binding affinity. Here, we present a stable aptamer ZAJ-2c and an environmentally sensitive aptamer ZAJ-2d optimized from an original cell-binding aptamer ZAJ-2, and the molecular target was further identified as CD49c on the cell membrane. ZAJ-2c was characterized with high binding ability independent of the presence of divalent cations at a temperature range from 4 to 37 °C, showing promise for measuring the expression of CD49c on cancer cells. Moreover, ZAJ-2d had a nanomolar binding affinity in the binding buffer at 4 °C, the same as ZAJ-2c, but lost the binding ability in a PBS buffer supplemented with 5 mM EDTA at 37 °C. This aptamer variant proved to selectively capture and release the CD49c positive cells by simply adjusting the temperatures and divalent cations. This set of aptamers might provide a toolbox for monitoring and operating of a wide range of cancer cells with CD49c expression on the surface, which will be helpful for the studying the heterogeneity of rare cells.