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Simple Summary: Numerous genetic mutations have been documented in HCC, and associated with clinical characters. Herein, we demonstrated that XIRP2 mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis and drug resistance. The presence of the XIRP2 mutation leads to enhanced stability of the XIRP2 protein, whereas its depletion significantly heightens sensitivity to oxaliplatin by inducing an excessive influx of zinc and calcium ions. XIRP2 mutation holds potential as a prognostic biomarker and that targeting the XIRP2 protein may offer therapeutic benefits in the management of HCC. Hepatocellular carcinoma (HCC) is a prevalent malignant digestive tumor. Numerous genetic mutations have been documented in HCC, yet the clinical significance of these mutations remains largely unexplored. The objective of this study is to ascertain the clinical value and biological effects of xin actin binding repeat containing 2 (XIRP2) mutation in HCC. The gene mutation landscape of HCC was examined using data from the Cancer Genome Atlas and the International Cancer Genome Consortium databases. The prognostic significance of the XIRP2 mutation was assessed through KM plot analysis. The association between drug sensitivity and the XIRP2 mutation was investigated using the TIDE algorithm and CCK-8 experiments. The biological effects of the XIRP2 mutation were evaluated through qRT-PCR, protein stability experiments, and relevant biological experiments. The XIRP2 mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis. A total of 72 differentially expressed genes (DEGs) were observed in HCC tissues with the XIRP2 mutation as compared to those with the XIRP2 wildtype, and these DEGs were closely related to ion metabolic processes. The XIRP2 mutation was linked to alterations in the sensitivity of fludarabine, oxaliplatin, WEHI-539, and LCL-161. CCK-8 assays demonstrated that HCC cells carrying the XIRP2 mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the XIRP2 wildtype. The XIRP2 mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of XIRP2 resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the XIRP2 mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin. [ABSTRACT FROM AUTHOR]

Background: N1-methyladenosine (m1A), among the most common internal modifications on RNAs, has a crucial role to play in cancer development. The purpose of this study were systematically investigate the modification characteristics of m1A in hepatocellular carcinoma (HCC) to unveil its potential as an anticancer target and to develop a model related to m1A modification characteristics with biological functions. This model could predict the prognosis for patients with HCC. Methods: An integrated analysis of the TCGA-LIHC database was performed to explore the gene signatures and clinical relevance of 10 m1A regulators. Furthermore, the biological pathways regulated by m1A modification patterns were investigated. The risk model was established using the genes that showed differential expression (DEGs) between various m1A modification patterns and autophagy clusters. These in vitro experiments were subsequently designed to validate the role of m1A in HCC cell growth and autophagy. Immunohistochemistry was employed to assess m1A levels and the expression of DEGs from the risk model in HCC tissues and paracancer tissues using tissue microarray. Results: The risk model, constructed from five DEGs (CDK5R2, TRIM36, DCAF8L, CYP26B, and PAGE1), exhibited significant prognostic value in predicting survival rates among individuals with HCC. Moreover, HCC tissues showed decreased levels of m1A compared to paracancer tissues. Furthermore, the low m1A level group indicated a poorer clinical outcome for patients with HCC. Additionally, m1A modification may positively influence autophagy regulation, thereby inhibiting HCC cells proliferation under nutrient deficiency conditions. Conclusions: The risk model, comprising m1A regulators correlated with autophagy and constructed from five DEGs, could be instrumental in predicting HCC prognosis. The reduced level of m1A may represent a potential target for anti-HCC strategies. [ABSTRACT FROM AUTHOR]

Hypoxia is involved in the development of pancreatic cancer (PC). The responses of hypoxia‐associated genes and their regulated mechanisms are largely unknown. In this study, through bioinformatic analysis and quantitative real‐time polymerase chain reaction, the YEATS domain containing 2 (YEATS2) was determined to be a key hypoxia‐associated gene. It was increased in PC cells under hypoxia, upregulated in PC tissues, and predicted poor outcome. YEATS2 inhibition decreased the proliferation and migration of PC cells under both normoxia and hypoxia in vitro as well as proliferation and metastasis in vivo. We found that hypoxia‐inducible factor 1α (HIF1α) regulated the expression of YEATS2 via binding to the hypoxia response element (HRE) of YEATS2 and coexpressed with YEATS2 in PC tissues. Overexpression of YEATS2 blocked the inhibitory effects of HIF1α silence on PC cell proliferation and migration under hypoxia. Collectively, our study revealed that YEATS2 is a target gene of HIF1α and promotes PC development under hypoxia. [ABSTRACT FROM AUTHOR]

RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HER2 overexpression is associated with various tumor types and prompted the development of targeted therapies. Previously, iso -[ 211 At]SGMAB-5F7 was developed as a HER2-targeted alpha therapy agent, demonstrating promising therapeutic efficacy in the preclinical stage. Aiming for an 18 F-labeled tracer for companion diagnostics in clinical translation, we employed the Al 18 F-RESCA strategy in our current work and investigated whether [ 18 F]AlF-RESCA-5F7 could visualize HER2 expression in vivo . [ 18 F]AlF-RESCA-5F7 was attained with high radiochemical purity (> 99%) and molar activity in the range of 16.5 ± 8.8 GBq/μmol (n = 8). Compared to previously reported radiotracers that contained 5F7 as the HER2-targeting carrier and fluorine-18 as the positron-emitting isotope, the radiosynthesis was simplified to one single step within 30 min. The dissociation constant of [ 18 F]AlF-RESCA-5F7 was determined as 3.3 nM via saturation binding assay using SKOV3 ovarian carcinoma cells. Tumor uptake of the novel tracer in Balb/c nude mice bearing SKOV3 xenografts was 4.69 ± 1.51, 3.34 ± 0.82 and 3.77 ± 0.99 %ID/g at 1, 2, and 4 h post-injection. Even though high retention of radioactivity was seen in the kidneys, micro-PET/CT imaging of [ 18 F]AlF-RESCA-5F7 delineated the tumor up to 4 h post-injection with minimal activity in the gallbladder, intestines, and bone. This study suggests that [ 18 F]AlF-RESCA-5F7 is a promising HER2 PET radiotracer with an eased radiolabeling method. Whether [ 18 F]AlF-RESCA-5F7 could work as a companion diagnostic agent to assist in patient stratification and treatment monitoring of iso -[ 211 At]SGMAB-5F7 warrants further investigation., Competing Interests: None., (AJNMMI Copyright © 2024.)

The follicle is the basic structural and functional unit of the ovary in female mammals. The excessive depletion of follicles will lead to diminished ovarian reserve or even premature ovarian failure, resulting in diminished ovarian oogenesis and endocrine function. Excessive follicular depletion is mainly due to loss of primordial follicles. Our analysis of published human ovarian single-cell sequencing results by others revealed a significant increase in rho-associated protein kinase 1 (ROCK1) expression during primordial follicle development. However, the role of ROCK1 in primordial follicle development and maintenance is not clear. This study revealed a gradual increase in ROCK1 expression during primordial follicle activation. Inhibition of ROCK1 resulted in reduced primordial follicle activation, decreased follicular reserve, and delayed development of growing follicles. This effect may be achieved through the HIPPO pathway. The present study indicates that ROCK1 is a key molecule for primordial follicular reserve and follicular development. NEW & NOTEWORTHY ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction.

Liquid biopsy (LB), as a minimally invasive method of gleaning insight into the dynamics of diseases through a patient fluid sample, represents an interesting tool that can advise in disease monitoring, treatment selection, early diagnosis, evaluation of the response, and prognosis. Cancer immunotherapy is a breakthrough in cancer treatment, which is now recognized as the "fourth pillar" of cancer treatment, after surgery, chemotherapy, and radiotherapy. Liquid biopsy offers a different befalling for beneath invasive diagnosis, real-time accommodating monitoring, and analysis options, involving the isolation of circulating biomarkers, such as cell-free DNA (cfDNA), circulating tumor cells (CTCs), exosomes, and microRNAs (miRNAs). The biomarkers herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine. Liquid biopsy offers an alternative, less invasive approach to select cancer patients who would benefit from immunotherapy and to monitor patients during their disease course. This review focuses on the use of liquid biopsy in the immunotherapy treatment of patients with cancer. In this review, we addressed the different promising liquid biopsy-based biomarkers in cancer patients that enable the selection of patients who benefit from immunotherapy and the monitoring of patients during this therapy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

In female mammals, the size of the initially established primordial follicle pool within the ovaries determines the reproductive life span. Interestingly, the establishment of the primordial follicle pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Here, we identify a new role of ASH1-like histone lysine methyltransferase (ASH1L) in controlling the apoptosis of oocytes during meiotic prophase I in mice. Our results showed that overexpression of Ash1l led to a dramatic loss of fetal oocytes via apoptosis, which subsequently resulted in a reduced capacity of the primordial follicle pool. Overexpression of Ash1l also led to a deficiency in DNA double-strand break repair associated with premature upregulation of p63 and phosphorylated checkpoint kinase 2 (p-CHK2), the major genome guardian of the female germline, following Ash1l overexpression in fetal ovaries. In summary, ASH1L is one of the indispensable epigenetic molecules that acts as a guardian of the genome. It protects oocyte genome integrity and removes oocytes with serious DNA damage by regulating the expression of p63 and p-CHK2 during meiotic prophase I in mice. Our study provides a perspective on the physiological regulatory role of DNA damage checkpoint signaling in fetal oocyte guardianship and female fertility.