• ECM
• LX‐2 human stellate cells
• Smad3
• TGFβ1
• collagen III
• p53
• Δ40p53 isoform

• Humans
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/drug effects
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Transforming Growth Factor beta1/pharmacology
• Transforming Growth Factor beta1/metabolism
• Protein Isoforms/metabolism
• Protein Isoforms/genetics
• Smad3 Protein/metabolism
• Collagen Type III/genetics
• Collagen Type III/metabolism
• Cell Line
• Signal Transduction
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Extracellular Matrix/metabolism

• RS-2023-00246207 Ministry of Education
• RS-2023-00301938 Ministry of Education
• Ministry of Education

• DNA repair
• gastrointestinal cancers
• genetic alterations
• p53‐MDM2
• signal transduction

• Proto-Oncogene Proteins c-mdm2/metabolism
• Proto-Oncogene Proteins c-mdm2/chemistry
• Humans
• Tumor Suppressor Protein p53/metabolism
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/pathology
• Animals

• Science and Engineering Research Board

• E2F
• PDZ-binding kinase
• anticancer drug
• apoptosis
• molecular-targeted therapy
• oral squamous cell carcinoma

• Animals
• Mice
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Mouth Neoplasms/drug therapy
• Mouth Neoplasms/genetics
• Mouth Neoplasms/metabolism
• Apoptosis
• Cell Proliferation/genetics
• Thiophenes
• Quinolones
• Mitogen-Activated Protein Kinase Kinases

• HF03-2021-0012 Hori Science and Arts Foundation
• 18K08342 Japan Society for the Promotion of Science
• 19K08668 Japan Society for the Promotion of Science
• 19K09292 Japan Society for the Promotion of Science
• 21K08426 Japan Society for the Promotion of Science

• breast cancer
• preclinical research
• experimental models of disease
• cancer stem cells
• cellular imaging

• Animals
• Mice
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Cell Line, Tumor
• Doxorubicin/pharmacology
• Doxorubicin/therapeutic use
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Protein Isoforms/metabolism
• Neoplasms

• Cancer Institute NSW (Cancer Institute New South Wales)
• Hunter Cancer Research Alliance (HCRA)
• Hunter Medical Research Institute (HMRI)
• University of Newcastle Australia (UON)
• The Iwanowska Programme, The Polish National Agency for Academic Exchange PPN/IWA/2018/1/00005

• Effect on cellular processes
• LINC00176 regulation
• lncRNA-miRNA axis
• p53 isoform
• Δ40p53 function

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Protein Isoforms/genetics
• Cell Cycle
• RNA, Messenger/genetics
• RNA, Long Noncoding/genetics
• Cell Proliferation/genetics
• Cell Line, Tumor

• breast cancer
• dna damage and repair
• apoptosis

Among the top ten deadly solid tumors are the two most frequent liver cancers, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, whose development and malignancy are favored by multifactorial conditions, which include aberrant maturation of pre-mRNA due to abnormalities in either the machinery involved in the splicing, i.e., the spliceosome and associated factors, or the nucleotide sequences of essential sites for the exon recognition process. As a consequence of cancer-associated aberrant splicing in hepatocytes- and cholangiocytes-derived cancer cells, abnormal proteins are synthesized. They contribute to the dysregulated proliferation and eventually transformation of these cells to phenotypes with enhanced invasiveness, migration, and multidrug resistance, which contributes to the poor prognosis that characterizes these liver cancers.

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

• alternative splicing
• carcinogenesis
• chemotherapy
• cholangiocarcinoma
• hepatocellular carcinoma
• metastasis
• multidrug resistance

All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long‐term survival of multicellular organisms (animals) in response to an ever‐changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.

• homeostasis
• immune response
• inflammation
• p53 isoforms
• pathogen

Breast cancer is the most diagnosed malignancy in women, with over half a million women dying from this disease each year. In our previous studies, ∆40p53, an N‐terminally truncated p53 isoform, was found to be upregulated in breast cancers, and a high ∆40p53 : p53α ratio was linked with worse disease‐free survival. Although p53α inhibits cancer migration and invasion, little is known about the role of ∆40p53 in regulating these metastasis‐related processes and its role in contributing to worse prognosis. The aim of this study was to assess the role of ∆40p53 in breast cancer migration and invasion. A relationship between Δ40p53 and gene expression profiles was identified in oestrogen‐receptor‐positive breast cancer specimens. To further evaluate the role of Δ40p53 in oestrogen‐receptor‐positive breast cancer, MCF‐7 and ZR75‐1 cell lines were transduced to knockdown p53α or Δ40p53 and overexpress Δ40p53. Proliferation, migration and invasion were assessed in the transduced sublines, and gene expression was assessed through RNA‐sequencing and validated by reverse‐transcription quantitative PCR. Knockdown of both p53α and ∆40p53 resulted in increased proliferation, whereas overexpression of ∆40p53 reduced proliferation rates. p53α knockdown was also associated with increased cell mobility. ∆40p53 overexpression reduced both migratory and invasive properties of the transduced cells. Phenotypic findings are supported by gene expression data, including differential expression of LRG1, HYOU1, UBE2QL1, SERPINA5 and PCDH7. Taken together, these results suggest that, at the basal level, ∆40p53 works similarly to p53α in suppressing cellular mobility and proliferation, although the role of Δ40p53 may be cell context‐specific.

• breast cancer
• gene expression
• migration and invasion
• p53
• Δ40p53

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboring FLT3-ITD, the therapeutic effect is limited. Here, to explore alternative therapeutics, we established a cellular model of monoallelic FLT3^ITD/WT cells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevated CD52 expression in K562–FLT3^ITD/WT cells compared to K562–FLT3^WT/WT cells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression of CD52 in K562–FLT3^ITD/WT cells was decreased in wild-type FLT3 (FLT3-WT) knock-in K562–FLT3^ITD/WT cells. In K562–FLT3^ITD/WT cells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Notably, an anti-CD52 antibody, alemtuzumab, induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) in K562-FLT3^ITD/WT cells compared to K562–FLT3^WT/WT cells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562–FLT3^ITD/WT cells in severe combined immunodeficiency (SCID) mice. Taken together, our data suggested that genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562–FLT3^ITD/WT cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation.

• cell biology
• stem cells

• B-Lymphocytes/metabolism
• B-Lymphocytes/pathology
• CRISPR-Cas Systems/genetics
• Cell Differentiation/genetics
• Cell Line, Tumor
• Chromosome Aberrations
• Chromosomes, Human, Pair 11/genetics
• Chromosomes, Human, Pair 14/genetics
• Cyclin D1/genetics
• Hematopoietic Stem Cells
• Humans
• Immunoglobulin Heavy Chains/genetics
• In Situ Hybridization, Fluorescence
• Induced Pluripotent Stem Cells/metabolism
• Induced Pluripotent Stem Cells/pathology
• Multiple Myeloma/genetics
• Translocation, Genetic/genetics
• Tumor Suppressor Protein p53/genetics
• VDJ Exons/genetics

• Grant-in-Aid for Young Scientists from the Japanese Ministry of Education, Culture, Sports, Science, and Technology
• Network-type Joint Usage/Research Center for Radiation Disaster Medical Science
• Grant-in-Aid for Scientific Research (C) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology
• The Japanese Society of Hematology Research Grant
• Japan Leukemia Research Fund

Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan–Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.

• PBK
• interleukin-6
• molecular-targeted therapy
• multiple myeloma
• tumor growth

• aging
• cancer
• p53
• p53 isoforms
• Δ40p53

Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS‐11, OCI‐My5, and ANBL‐6), we generated FAM46C^−/− cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C^−/− KMS‐11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C^−/− cell‐derived tumors than mice with the FAM46C^WT cell‐derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C^−/− cells compared to WT cells. In addition, caspase activities decreased in the FAM46C^−/− cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum‐responsive genes while inactivating phosphatase and tensin homolog (PTEN)‐related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF‐04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C^−/− MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K‐Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene.

• FAM46C
• PI3K-Akt
• multiple myeloma
• tumor suppressor
• tumorigenesis

• IGF2
• TLR2
• ameloblastoma
• gene expression
• proliferation
• signaling pathway

• N-terminal modifications
• N-terminal proteoforms
• alternative splicing
• alternative translation initiation
• protein N termini

Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

• ageing and age-related diseases
• cancer
• cellular senescence
• p53 isoform
• reprogramming

• Aging
• Animals
• Cellular Reprogramming
• Cellular Senescence
• Genes, p53
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• amyloid
• cancer biology
• endometrium carcinoma
• p53
• p53 isoforms
• p53 transactivation domain (TAD)
• protein aggregation
• protein misfolding

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.

• Alternative isoforms
• Transcription factors
• Hepatocellular carcinoma
• Alternative splicing
• Hepatic differentiation
• Personalized treatment

In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are ∆40p53, ∆133p53, and ∆160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered ‘responsive elements’ than p53. Furthermore, they may exert a ‘dominant negative effect’ or induce more aggressive cancer by the ‘gain of function’. One possible mechanism of p53 inactivation can be through tetramerization with the ∆133p53 and ∆160p53 isoforms—both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation—possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms.

• aggregation
• cancer
• p53
• p53 isoform
• prion
• ∆133p53
• ∆160p53
• ∆40p53

• Diabetes mellitus
• Hepatocellular carcinoma
• Hyperglycemia
• Hyperinsulinemia
• Insulin resistance

• Cellular senescence
• Clinical implications
• Liver disease
• Molecular mechanism
• Therapeutic target

• Afuresertib
• Akt inhibitor
• Mesothelioma
• cancer therapy