Abstract

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.

Highlights

  • Hepatocellular carcinoma (HCC), as the most prevalent subtype of primary hepatic malignancy, has been ranked as the fourth leading cause of cancer-related mortality worldwide (Bray et al, 2018)

  • Our study demonstrates that integrin β1 (ITGB1) exerts a pivotal role in accelerating cell cycle via paxillin (PXN)/14-3-3 protein zeta (YWHAZ)/ protein kinase B (AKT) pathways, which provides a novel insight into the role of ITGB1 in HCC malignant progression

  • The findings indicated that ITGB1, which was markedly increased in HCC tumors compared to normal tissues, was progressively upregulated along with clinical stages of HCC patients from I to IV (Figure 1A, B)

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Summary

Introduction

Hepatocellular carcinoma (HCC), as the most prevalent subtype of primary hepatic malignancy, has been ranked as the fourth leading cause of cancer-related mortality worldwide (Bray et al, 2018). The majority of HCC are not detectable until they reach an advanced stage, rendering HCC patients ineligible for receiving curative therapies (Rasool et al, 2014). Being one of the most aggressive malignancies, HCC results in very poor clinical outcomes in patients, whose overall 5-year survival rate is estimated to be extremely low (Hu et al, 2019). Accumulating evidence implicates that ITGB1 is aberrantly expressed in multiple cancer types, including breast cancer, lung cancer, gastric cancer, prostate cancer, pancreatic cancer, colorectal cancer, and laryngeal cancer, and contributes to malignant phenotypes of tumors by mediating cell migration, invasion, survival, and apoptosis (Bogorad et al, 2014; Li et al, 2018; Sun et al, 2018)

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