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Integrin subunit beta 8 contributes to lenvatinib resistance in HCC.

ABSTRACT: Lenvatinib is a multikinase inhibitor approved as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the underlying mechanisms governing this resistance are largely unknown. In this study, we established two lenvatinib-resistant (LR) HCC cell lines and identified integrin subunit beta 8 (ITGB8) as a critical contributor to lenvatinib resistance in HCC. The elevated expression of ITGB8 was observed in LR HCC cells. Furthermore, silencing of ITGB8 reversed lenvatinib resistance in vitro and in vivo, whereas ectopic expression of ITGB8 in lenvatinib-sensitive parental HCC cells exhibited increased resistance to lenvatinib. Mechanistically, ITGB8 regulated lenvatinib resistance through an HSP90-mediated stabilization of AKT and enhanced AKT signaling. In support of this model, either an AKT inhibitor MK-2206 or an HSP90 inhibitor 17-AAG resensitized LR HCC cells to lenvatinib treatment. Conclusion: Collectively, our results establish a crucial role of ITGB8 in lenvatinib resistance, and suggest that targeting the ITGB8/HSP90/AKT axis is a promising therapeutic strategy in patients with HCC exhibiting lenvatinib resistance.

SUBMITTER: Hou W

PROVIDER: S-EPMC9234648 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin.

Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Lenvatinib oral chemotherapy is approved as a first-line treatment of patients with unresectable HCC. The efficacy and therapeutic duration of lenvatinib are limited by drug resistance, and the mechanism is unclear. IRF2 is a constitutive transcription factor associated with the development of various cancers by regulating cancer cell growth, apoptosis, and drug resistance. However, the potential role of IRF2 in lenvatinib resistance in HCC has not been explored. In this study, we found that IRF2 promoted proliferation, inhibited apoptosis, and increased lenvatinib resistance of HCC cells by regulating β-catenin expression. Silencing IRF2 downregulated the expression of β-catenin, while overexpressing IRF2 upregulated β-catenin. Moreover, the expression of β-catenin and IRF2 was positively correlated in HCC tissues. Inhibiting β-catenin with XAV-939 effectively abrogated β-catenin expression caused by lenvatinib treatment. These findings identify an important function of IRF2 in HCC and demonstrate a mechanism of lenvatinib resistance of HCC cells. Targeting IRF2 may be a potential strategy to improve the therapeutic effect of lenvatinib on HCC.

| S-EPMC7988337 | biostudies-literature

Cloning of an integrin beta subunit exhibiting high homology with integrin beta 3 subunit.

Project description:cDNAs for another beta subunit of the integrin family were isolated with the aid of polymerase chain reaction and sequenced. The combined cDNA sequence is 3110 base pairs (bp) in size and has one long open reading frame of 2388 bp. The deduced amino acid sequence is similar to those of other integrin beta subunits but does not correspond to beta 1, beta 2, beta 3, or beta 4 subunits. This beta subunit is divided by a membrane-spanning domain into a large extracellular domain at the N-terminal side and a small intracellular domain at the C-terminal side. The extracellular domain has a cysteine-rich region that contains four repeats of 8-cysteine motifs. All 56 cysteine residues found in the extracellular domains of other mature beta subunits are present in this beta subunit. The beta subunit reported here has particularly high homology with the beta 3 subunit. The mRNA for the molecule is approximately 3.5 kbp in size and is expressed in various cell types. Other researchers have recently reported additional beta subunits that associate with the vitronectin receptor alpha subunit. The deduced amino acid sequence of this molecule contains the N-terminal partial amino acid sequence of one of these beta subunits, beta x. The beta subunit described herein seems to be identical to the beta x subunit and to function as the beta subunit of a vitronectin receptor.

| S-EPMC54322 | biostudies-other

Identification of integrin beta subunit mutations that alter affinity for extracellular matrix ligand.

Project description:We examined over 50 mutations in the Drosophila βPS integrin subunit that alter integrin function in situ for their ability to bind a soluble monovalent ligand, TWOW-1. Surprisingly, very few of the mutations, which were selected for conditional lethality in the fly, reduce the ligand binding ability of the integrin. The most prevalent class of mutations activates the integrin heterodimer. These findings emphasize the importance of integrin affinity regulation and point out how molecular interactions throughout the integrin molecule are important in keeping the integrin in a low affinity state. Mutations strongly support the controversial deadbolt hypothesis, where the CD loop in the β tail domain acts to restrain the I domain in the inactive, bent conformation. Site-directed mutations in the cytoplasmic domains of βPS and αPS2C reveal different effects on ligand binding from those observed for αIIbβ3 integrins and identify for the first time a cytoplasmic cysteine residue, conserved in three human integrins, as being important in affinity regulation. In the fly, we find that genetic interactions of the βPS mutations with reduction in talin function are consistent with the integrin affinity differences measured in cells. Additionally, these genetic interactions report on increased and decreased integrin functions that do not result in affinity changes in the PS2C integrin measured in cultured cells.

| S-EPMC3162457 | biostudies-literature

An alternative cytoplasmic domain of the integrin beta 3 subunit.

Project description:A cDNA encoding a new form of the shared beta subunit (beta 3) of the platelet integrin gpIIb/IIIa and the vitronectin receptor was isolated from a placental cDNA library by screening with a beta 3 (gpIIIa) DNA probe. This beta 3 variant differs from the previously reported beta 3 in that the cytoplasmic domain is 8 amino acids shorter and has an alternative, 13-amino acid COOH-terminal peptide. The 3' untranslated region of the cDNA also differs from the previously reported sequence, while the region coding for the transmembrane domain and extracellular domain is identical to it. Reverse transcription combined with polymerase chain reaction was used to show that human placental tissue and two human cell lines contain the variant mRNA. The sequences of the cDNAs for the previously known beta 3 and the variant beta 3 described here suggest that the difference between the cytoplasmic domains of these subunits arises as a result of an alternative mRNA splicing. These cytoplasmic domains may provide alternative means for the beta 3 integrins to interact with cytoskeletal components.

| S-EPMC297633 | biostudies-other

Requirement of alpha and beta subunit transmembrane helix separation for integrin outside-in signaling.

Project description:Adhesion to extracellular ligands through integrins regulates cell shape, migration, growth, and survival. How integrins transmit signals in the outside-to-in direction remains unknown. Whereas in resting integrins the alpha and beta subunit transmembrane domains are associated, ligand binding promotes dissociation and separation of these domains. Here we address whether such separation is required for outside-in signaling. By introduction of an intersubunit disulfide bond, we generated mutant integrin alphaIIbbeta3 with blocked transmembrane separation that binds ligand, mediates adhesion, adopts an extended conformation after ligand binding, and forms antibody-induced macroclusters on the cell surface similarly to wild type. However, the mutant integrin exhibits a profound defect in adhesion-induced outside-in signaling as measured by cell spreading, actin stress-fiber and focal adhesion formation, and focal adhesion kinase activation. This defect was rescued by reduction of the disulfide bond. Our results demonstrate that the separation of transmembrane domains is required for integrin outside-in signal transduction.

| S-EPMC1988953 | biostudies-literature

Role of the beta-subunit arginine/lysine finger in integrin heterodimer formation and function.

Project description:Formation of the integrin alphabeta heterodimer is essential for cell surface expression and function. At the core of the alphabeta interface is a conserved Arg/Lys "finger" from the beta-subunit that inserts into a cup-like "cage" formed of two layers of aromatic residues in the alpha-subunit. We evaluated the role of this residue in heterodimer formation in an alphaA-lacking and an alphaA-containing integrin alphaVbeta3 and alphaMbeta2 (CD11b/CD18), respectively. Arg261 of beta3 was mutated to Ala or Glu; the corresponding Lys252 of beta2 was mutated to Ala, Arg, Glu, Asp, or Phe; and the effects on heterodimer formation in each integrin examined by ELISA and immunoprecipitation in HEK 293 cells cotransfected with plasmids encoding the alpha- and beta-subunits. The Arg261Glu (but not Arg261Ala) substitution significantly impaired cell surface expression and heterodimer formation of alphaVbeta3. Although Lys252Arg, and to a lesser extent Lys252Ala, were well tolerated, each of the remaining substitutions markedly reduced cell surface expression and heterodimer formation of CD11b/CD18. Lys252Arg and Lys252Ala integrin heterodimers displayed a significant increase in binding to the physiologic ligand iC3b. These data demonstrate an important role of the Arg/Lys finger in formation of a stable integrin heterodimer, and suggest that subtle changes at this residue affect the activation state of the integrin.

| S-EPMC3075857 | biostudies-literature

RNA-seq data for parental and lenvatinib-resistant HCC cells

Project description:RNA-seq data for parental and lenvatinib-resistant HCC (Hep3B, Huh7) cells

2022-03-23 | GSE186191 | GEO

Single cell RNA sequencing of immune cells from lenvatinib-resistant mouse HCC model after lenvatinib or combined lenvatinib and CDK4/6 inhibitor palbociclib treatment

Project description:We used single-cell RNA sequencing (scRNA seq) to elucidate the alterations of tumor microenvironment upon combined treatment of lenvatinib and palbociclib (combo).

2023-09-27 | GSE218010 | GEO

Impact of modified albumin-bilirubin grade on survival in patients with HCC who received lenvatinib.

Project description:We investigated the impact on survival of modified albumin-bilirubin (mALBI) grade versus Child-Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child-Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944-3.141 and HR, 2.178; 95%CI, 1.591-2.982]. In patients with a Child-Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083-3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child-Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child-Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child-Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

| S-EPMC8280227 | biostudies-literature

The size of the intracellular beta 1-integrin precursor pool regulates maturation of beta 1-integrin subunit and associated alpha-subunits.

Project description:A large pool of precursor beta 1-integrin subunits is frequently found intracellularly. During malignant transformation this pool often disappears. Concomitantly, integrin-mediated cell-adhesion functions are disturbed, even though no change in the number of beta 1-integrin receptors on the cell surface can be observed. Here, we have studied the role of an intracellular pre-beta 1-integrin pool by transfecting human MG-63 osteosarcoma cells with plasmid construction producing an antisense RNA for the beta 1-integrin subunit. Stable cell clones expressing beta 1-integrin antisense RNA were shown to have a reduced intracellular pool of pre-beta 1-integrin subunits. In the antisense-transfected cells, the synthesis of the beta 1-integrin chain was reduced by 65% compared with non-transfected or vector-transfected MG-63 cells. The decreased synthesis of the beta 1-integrin chain was associated with accelerated maturation of the beta 1-integrin chain (half-maturation time about 5 h in antisense-transfected cells compared with about 10.5 h in control cells), whereas maturation of the alpha-integrin chain slowed down. The amount of beta 1-integrins on the cell surface, however, remained unaltered. Cell clones with the largest decrease in the relative amount of the pre-beta 1-integrin subunit also showed altered integrin function. They were found to synthesize fibronectin, but were unable to assemble it into a fibronectin matrix on the cell surface. Thus we conclude that the repression of biosynthesis of the beta 1-integrin chain leads to alterations in receptor maturation and may be connected with altered receptor function.

| S-EPMC1138233 | biostudies-other

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