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Amniotic epithelial stem cells (AESCs) are considered as potential alternatives to keratinocytes (KCs) in tissue-engineered skin substitutes used for treating skin damage. However, their clinical application is limited since similarities and distinctions between AESCs and KCs remain unclear. Herein, a transcriptomics analysis and functional evaluation were used to understand the commonalities and differences between AESCs and KCs. RNA-sequencing revealed that AESCs are involved in multiple epidermis-associated biological processes shared by KCs and show more similarity to early stage immature KCs than to adult KCs. However, AESCs were observed to be heterogeneous, and some possessed hybrid mesenchymal and epithelial features distinct from KCs. A functional evaluation revealed that AESCs can phagocytose melanosomes transported by melanocytes in both 2D and 3D co-culture systems similar to KCs, which may help reconstitute pigmented skin. The overexpression of TP63 and activation of NOTCH signaling could promote AESC stemness and improve their differentiation features, respectively, bridging the gap between AESCs and KCs. These changes induced the convergence of AESC cell fate with KCs. In future, modified reprogramming strategies, such as the use of small molecules, may facilitate the further modulation human AESCs for use in skin regeneration. [ABSTRACT FROM AUTHOR]

In developing mammalian telencephalon, the loss of adherens junctions and cell cycle exit represent crucial steps in the differentiation of neuroepithelial cells into neurons, but the relationship between these cellular events remains obscure. Atypical protein kinase C (aPKC) is known to contribute to junction formation in epithelial cells and to cell fate determination for Drosophila neuroblasts. To elucidate the functions of aPKCλ, one out of two aPKC members, in mouse neocortical neurogenesis, a Nestin-Cre mediated conditional gene targeting system was employed. In conditional aPKCλ knockout mice, neuroepithelial cells of the neocortical region lost aPKCλ protein at embryonic day 15 and demonstrated a loss of adherens junctions, retraction of apical processes and impaired interkinetic nuclear migration that resulted in disordered neuroepithelial tissue architecture. These results are evidence that aPKCλ is indispensable for the maintenance of adherens junctions and may function in the regulation of adherens junction integrity upon differentiation of neuroepithelial cells into neurons. In spite of the loss of adherens junctions in the neuroepithelium of conditional aPKCλ knockout mice, neurons were produced at a normal rate. Therefore, we concluded that, at least in the later stages of neurogenesis, regulation of cell cycle exit is independent of adherens junctions. [ABSTRACT FROM AUTHOR]

During an immune response against a microbial pathogen, activated naive T lymphocytes give rise to effector cells that provideacute host defense and memory cells that provide long-lived immunity. It has been shown that T lymphocytes can undergo asymmetricdivision, enabling the daughter cells to inherit unequal amounts of fate-determining proteins and thereby acquire distinctfates from their inception. In this study, we show that the absence of the atypical protein kinase C (PKC) isoforms, PKCζ and PKCλ/ι,disrupts asymmetric CD8+ T lymphocyte division. These alterations were associated with aberrant acquisition of a pre-effectortranscriptional program, detected by single-cell gene expression analyses, in lymphocytes that had undergone their first divisionin vivo and enhanced differentiation toward effector fates at the expense of memory fates. Together, these results demonstrate a role for atypical PKC in regulating asymmetric division and the specification of divergent CD8+ T lymphocyte fates early during animmune response. [ABSTRACT FROM AUTHOR]

Background/aim: Patients with triple-negative breast cancer (TNBC) have a high rate of recurrence within 3 years of diagnosis and a high rate of death within 5 years compared to other subtypes. The number of clinical trials investigating various new agents and combination therapies has recently increased; however, current strategies benefit only a minority of patients. This study aimed to identify specific genes that predict patients at high risk of recurrence and the immune status of the tumor microenvironment at an early stage, thereby providing insight into potential therapeutic targets to improve clinical outcomes in TNBC patients., Materials and Methods: We evaluated the prognostic significance of microarray mRNA expression of 20,603 genes in 233 TNBC patients from the METABRIC dataset and further validated the results using RNA-seq mRNA expression data in 143 TNBC patients from the GSE96058 dataset., Results: Eighteen differentially expressed genes (AKNA, ARHGAP30, CA9, CD3D, CD3G, CD6, CXCR6, CYSLTR1, DOCK10, ENO1, FLT3LG, IFNG, IL2RB, LPXN, PRKCB, PVRIG, RASSF5, and STAT4) identified in both datasets were found to be reliable biomarkers for predicting TNBC recurrence and progression. Notably, the genes whose low expression was associated with increased risk of recurrence and death were immune-related genes, with significant differences in levels of immune cell infiltration in the tumor microenvironment between high- and low- expression groups., Conclusion: Genes reported herein may be effective biomarkers to identify TNBC patients who will and will not benefit from immunotherapy and may be particularly important genes for developing future treatment strategies, including immunotherapy., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We have reported that p62 (also known as sequestosome 1) is needed for survival/proliferation and tumor formation by aldehyde dehydrogenase 1 (ALDH1) -positive cancer stem cells (CSCs) and that p62 high ALDH1A3 high expression is associated with a poor prognosis in luminal B breast cancer. However, the association between p62 high ALDH1A3 high and the benefit from radiotherapy in patients with luminal B breast cancer remains unclear., Materials and Methods: Datasets from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) were downloaded, and data from p62 high ALDH1A3 high luminal B patients treated without or with radiotherapy were analyzed by Kaplan-Meier and multivariate Cox regression analyses. We also performed an in vitro tumor sphere formation assay after X-ray irradiation using p62-knockdown ALDH1 high luminal B BT-474 cells., Results: p62 high ALDH1A3 high patients had poorer clinical outcomes than other luminal B breast cancer patients treated with radiotherapy. The combination of p62 DsiRNA KD and X-ray irradiation suppressed in vitro tumor sphere formation by ALDH1 high BT-474 cells. These results suggest that p62 is involved in the reduced effect of X-ray irradiation on ALDH1-positive luminal B breast CSCs., Conclusion: p62 and ALDH1A3 may serve as prognostic biomarkers for luminal B breast cancer patients treated with radiotherapy. Additionally, the combination of p62 inhibition and radiotherapy could be useful for targeted strategies against ALDH1-positive luminal B breast CSCs., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer., Patients and Methods: This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively., Results: Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047)., Conclusion: ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: CD58 is an immune adhesion molecule on the cellular surface. It was previously found that a high expression of CD58 predicted a poor prognosis of patients with lower-grade gliomas. Therefore, the aim of this paper was to investigate the association between CD58 and breast cancer., Materials and Methods: CD58 gene expression data downloaded from cBioPortal was compared between the different subtypes of breast cancer. Clinical prognosis was examined using Kaplan-Meier analysis and multivariable Cox regression analysis. The association between CD58 expression and immune cell infiltration was estimated using the TIMER 2.0 web platform. Finally, the tumour sphere formation of aldehyde dehydrogenase 1 (ALDH1) high basal-like breast cancer stem cells in which CD58 was knocked down using siRNA was measured., Results: CD58 mRNA was mainly enriched in claudin-low and basal-like subtypes. The high expression of CD58 predicted a good prognosis in patients with luminal A and luminal B breast cancer. This prediction may be due to the association of immune cell infiltration with CD58. Notably, patients with luminal A breast cancer with a high expression of CD58 in association with ALDH1A3 exhibited a good prognosis; however, this did not apply to patients with basal-like breast cancer. The in vitro experiments revealed that knockdown of CD58 inhibited the tumour sphere formation ability of ALDH1 high basal-like cancer cells., Conclusion: CD58 may function as a potential prognostic biomarker and therapeutic target in ALDH-positive basal-like cancer stem cells., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers., Materials and Methods: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1 high cell viability and tumor-sphere formation., Results: c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Met high PKCλ high ALDH1A3 high have a poorer prognosis than patients with c-Met low PKCλ low ALDH1A3 low Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1 high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer., Conclusion: c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Breast cancer is one of the common malignant diseases among women in Japan as well as in western countries, and its incidence continues to increase. Normal mammary duct epithelial cells exhibit a well-organized apicobasal polarity, which forms the basis for their specific structure and function. Although the loss of epithelial cell polarity is one of the major changes that occur during the progression of tumor cells, including breast cancer, the underlying molecular mechanisms for this, as well as their relationship to other changes such as increased proliferation and metastasis, remain to be elucidated. The atypical protein kinase C lambda/iota (aPKC lambda/iota) is involved in several signal transduction pathways, including the establishment of epithelial cell polarity. In this study we evaluated the expression and localization of aPKC lambda/iota in breast cancer by immunohistochemistry and compared our findings with the clinicopathologic factors associated with the tumor specimens. We detected aPK Clambda/iota protein overexpression in 88 of the 110 breast cancer cases (80.0%) under study, expect for decreased expression in a few cases. The immunoreactivity of aPK Clambda/iota was generally weak in ductal carcinoma in situ, but strong in invasive ductal carcinoma (IDC; P = .022). The correlation between apical or cytoplasmic aPKC lambda/iota localization and tumor pathologic type (ie, atypical ductal hyperplasia, ductal carcinoma in situ. or IDC) was also demonstrated (P < .001). These results thus indicate that the normal apicobasal polarity is lost upon the progression of a breast lesion to IDC. This is also the first evidence to show aPKC lambda/iota overexpression in breast cancer and demonstrates that its localization is associated with the trend of pathologic type of the tumor.

The photoreceptor is a highly polarized neuron and also has epithelial characteristics such as adherens junctions. To investigate the mechanisms of polarity formation of the photoreceptor cells, we conditionally knocked out atypical protein kinase Clambda (aPKClambda), which has been proposed to play a critical role in the establishment of epithelial and neuronal polarity, in differentiating photoreceptor cells using the Cre-loxP system. In aPKClambda conditional knock-out (CKO) mice, the photoreceptor cells displayed morphological defects and failed to form ribbon synapses. Intriguingly, lack of aPKClambda in differentiating photoreceptors led to severe laminar disorganization not only in the photoreceptor layer but also in the entire retina. Cell fate determination was not affected by total laminar disorganization. After Cre recombinase began to be expressed in the developing photoreceptors at embryonic day 12.5, both the immature photoreceptors and mitotic progenitors were dispersed throughout the CKO retina. We detected that adherens junction formation between the immature photoreceptors and the progenitors was lost in the CKO retina, whereas it was maintained between the progenitors themselves. These results indicate that the expression of aPKClambda in differentiating photoreceptors is required for total retinal lamination. Our data suggest that properly polarized photoreceptors anchor progenitors at the apical edge of the neural retina, which may be essential for building correct laminar organization of the retina.

Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the lambda isoform of PKC in pancreatic beta cells (betaPKClambda(-/-) mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from betaPKClambda(-/-) mice. Neither the beta cell mass nor the islet insulin content of betaPKClambda(-/-) mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3beta was reduced in islets of betaPKClambda(-/-) mice, and the expression of genes regulated by HNF3beta was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3beta expression by infection of islets from betaPKClambda(-/-) mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKClambda plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for beta cell function.