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.

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: 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.

OBJECTIVE: To investigate the expression of ITGA3 and its association with clinical outcomes in papillary thyroid carcinoma (PTC).
METHODS: The expression level, association with clinicopathologic characteristics, co-expressed genes, signaling pathways of ITGA3 in thyroid cancer were comprehensively analyzed using bioinformatics analysis through multiple public gene databases. PTC specimens and cell lines were used to verify the results of bioinformatics analysis.
RESULTS: Data mining based on the Oncomine database revealed that ITGA3 expression in classical PTC and tall cell variant PTC was much higher than that in normal thyroid tissue except the follicular variant PTC. Analysis based on The Cancer Genome Atlas (TCGA) database showed that the expression of ITGA3 varies greatly in pathological stages, pathological types, tumor invasion stages, and lymph node metastasis stages of thyroid carcinoma. High expression level of ITGA3 was correlated with tumor regional invasion and lymph node metastasis. Multivariate analysis using logistic regression model showed that high expression of ITGA3 was a risk factor that associated with PTC recurrence and lymph node metastasis. Survival analysis showed that patients with high expression of ITGA3 in PTC had a poorer relapse-free survival (RFS) than patients with low expression of ITGA3 (P < 0.05). Immunohistochemistry experiments showed that the expression of ITGA3 in recurrent thyroid cancer tissues was stronger than that in no-recurrent thyroid cancer tissues (P < 0.05). Knockdown of ITGA3 by sh-RNA in PTC cell lines suppresses cell viability and invasive and migrating capacity.
CONCLUSIONS: ITGA3 is overexpressed in PTC, especially in those with higher tumor invasion grades and lymph node metastasis, and was associated with recurrence and poor RFS of PTC. High expression of ITGA3 may have the potential role of predicting PTC recurrence and lymph node metastasis.

OBJECTIVE: ILNEB (interstitial lung disease, nephrotic syndrome, epidermolysis bullosa) syndrome is caused by ITGA3 mutations. Demises usually happened at infancy. This study reports a complete ILNEB syndrome child with slow disease progression.
METHODS: Clinical data and related specimens were collected. Genomic DNA was extracted for genetic sequencing. Integrin α3 expression was detected by western blotting and immunofluorescence staining.
RESULTS: The patient was male. He experienced recurrent rashes shortly after birth. His sparse eyebrows and eyelashes gradually lost. The patient was vulnerable to respiratory infections and had recurrent fever after vaccine immunization after 4 years. He was found with nephrotic syndrome and polycystic renal dysplasia at 8 years and progressed to end-stage renal disease at 12 years. A chest Computed Tomography revealed intestinal lung disease at 8 years. Continuous oxygen supplementation was needed at 13 years. Counts of lymphocyte subsets revealed elevated percentage of double-negative T cells and activated T cells. Next-generation sequencing revealed a novel homozygous splice mutation c.2219 + 4A > Cin ITGA3 that was predicted to be deleterious. The mutation resulted in exon17 skipping with the loss of 80 bp in the mRNA. The aberrant integrin α3 mRNA level was lower compared to the healthy control. Integrin α3 protein was not detected in urine epithelial cells and skin of the patient.
CONCLUSIONS: We report a patient harboring a novel ITGA3 homozygous splice mutation who presented with complete ILNEB syndrome but slow disease progression. Immune disorders were suspected.

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.

BACKGROUND: PLEK2 (pleckstrin) could bind to membrane-bound phosphatidylinositols and further promote cell spread. Recently, several studies have noted the importance of PLEK2 in tumor metastasis. However, the role of PLEK2 in head and neck squamous cell carcinoma (HNSCC) remains to be elucidated.
METHODS: The PLEK2 expression in HNSCC was identified using Oncomine, Gene Expression Omnibus (GEO), UALCAN databases, and western blot analysis. Prognosis analysis was performed using Kaplan-Meier plotter, DriverDBv3, UALCAN, UCSC Xena, and GEO databases. Single-cell functional analysis was further performed using the cancerSEA database. The PLEK2-related co-expressed genes were identified, and gene set enrichment analysis was performed using LinkedOmics. Furthermore, the top 10 hub genes were identified using the cytoHubba plug-in of Cytoscape. Then, gene enrichment analysis, pathway activity, and drug sensitivity analyses of the hub genes were performed using the R package \"clusterProfiler\" and GSCAlite. Finally, the UCSC Xena browser was utilized to explore the hub gene most likely to play a synergic role with PLEK2 in HNSCC.
RESULTS: Elevated expression of PLEK2 was observed in HNSCC and even in HNSCC subgroups based on diverse clinicopathological features, portending a poor prognosis in HNSCC. PLEK2 was correlated with metastasis and hypoxia in HNSCC, and the PLEK2-related co-expressed genes were mainly involved in the focal adhesion pathway. The top 10 hub genes were primarily enriched in focal adhesion, HPV infection, ECM-receptor interaction, and PI3K-AKT signaling pathway, and epithelial-mesenchymal transition pathway was activated. Furthermore, the expression levels of the hub genes were associated with sensitivity and resistance to various small molecules and anti-cancer drugs. Further study suggested that ITGA3 and PLEK2 might be viewed as inextricably linked in facilitating HNSCC metastasis.
CONCLUSIONS: In general, PLEK2 might serve as a potential biomarker for the diagnosis of HNSCC and guide the development of targeted therapies for HNSCC.

Monocytes/macrophages are important target cells for HIV-1. Here, we investigated whether HIV-1 induces changes in the macrophage gene expression profile to support viral replication. We observed that the macrophage gene expression profiles dramatically changed upon HIV-1 infection. The majority of the HIV-1 regulated genes were also differentially expressed in M2a macrophages. The biological functions associated with the HIV-1 induced gene expression profile in macrophages were mainly related to inflammatory responses. CD9 and ITGA3 were among the top genes upregulated upon HIV-1 infection. We showed that these genes support viral replication and that downregulation of these genes decreased HIV-1 replication in macrophages. Here we showed that HIV-1 infection of macrophages induces a gene expression profile that may dampen inflammatory responses. CD9 and ITGA3 were among the top genes regulated by HIV-1 and were shown to support viral production most likely at the level of viral budding and release.

We describe a simple, non-invasive assay to identify fucosylated-glycoisoform of integrin alpha-3 (ITGA3) directly from unprocessed urine. ITGA3 was detected directly from the urine of bladder cancer (BlCa) (n = 13) and benign prostatic hyperplasia (BPH) (n = 9) patients with the use of lectins coated on europium-doped-nanoparticles (Eu3+-NPs). Lectin Ulex europaeus agglutinin-I (UEA) showed enhanced binding with BlCa-derived ITGA3. The evaluation with individual samples showed that a glycovariant ITGA3-UEA assay could significantly discriminate BlCa from BPH patients (p = 0.007). The detection of aberrantly fucosylated-isoform of ITGA3 from urine can be used to distinguish BlCa from age-matched benign controls in a simple sandwich assay.