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YAP1 Downregulation Impacts YTHDF3 and SMAD7 in BCSCs

KEY TAKEAWAYS

  • The study aimed to explore YAP1 knockdown’s effect on BCSCs, focusing on YTHDF3-mediated stabilization of SMAD7.
  • Researchers noticed that silencing YAP1 in BCSCs impedes YTHDF3-mediated degradation of m6A-modified SMAD7, resulting in reduced cell stemness.

The previous study established the oncogenic role of Yes-associated protein 1 (YAP1) in bladder cancer (BLCA). Building on this, the current research focuses on the effects of YAP1 on bladder cancer stem cells (BCSCs) and explores the underlying mechanisms involved.

Dandan Qiu and the team aimed to assess the impact of YAP1 knockdown on BCSCs, particularly examining how it influences YTHDF3-mediated degradation of m6A-modified SMAD7 and its subsequent effect on cell stemness.

They performed an inclusive analysis involving BCSCs derived from human BLCA cells (UMUC3) treated with cisplatin, identified by CD133+ expression via flow cytometry. They utilized bioinformatics to analyze YAP1 interaction proteins and N6-methyladenosine (m6A) modifications on mothers against decapentaplegic homolog 7 (SMAD7).

BCSCs were transfected, and subsequent analyses of SMAD7 m6A levels, YTH domain-containing family proteins 3 (YTHDF3)-SMAD7 interactions, and YAP1/YTHDF3 expression were conducted using methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and quantitative reverse transcription PCR (qRT-PCR). The proliferation of BCSCs was assessed through 5-Bromo-2-deoxyuridine (BrdU) staining.

Migration, invasion, and tumor sphere formation of UMUC3/BCSCs were evaluated using Transwell assays and tumor sphere formation assays. Western blot assays were employed to measure expressions of YAP1, YTHDF3, SMAD7, transforming growth factor (TGF)-β1, and stemness markers in UMUC3/BCSCs.

The BCSCs showed a higher CD133+ ratio, increased expressions of stemness markers, YAP1, YTHDF3, and TGF-β1, along with reduced SMAD7 expression and enhanced invasion, migration, and tumor sphere formation capabilities were observed compared to UMUC3 cells. YAP1 knockdown led to a decrease in SMAD7 m6A levels and disrupted the YTHDF3-SMAD7 interaction in BCSCs.

Silencing YAP1 resulted in reduced cell growth, invasiveness, migration, and tumor sphere formation, alongside lower levels of stemness-associated proteins, YTHDF3, and TGF-β1, while increasing SMAD7 expression in BCSCs. However, these effects were counteracted by YTHDF3 overexpression.

The study concluded that silencing YAP1 in BCSCs impedes the YTHDF3-mediated degradation of m6A-modified SMAD7, leading to a reduction in cell stemness.

No funding information was given for this source.

Source: https://pubmed.ncbi.nlm.nih.gov/39054719/

Qiu D, Gao L, Yu X. (2024). “Knockdown of YAP1 Reduces YTHDF3 to Stabilize SMAD7 and thus Inhibit Bladder Cancer Stem Cell Stemness.” Discov Med. 2024;36(186):1486-1498. doi:10.24976/Discov.Med.202436186.138

KRT23 Identified as Key Target in BLCA Immunotherapy

KEY TAKEAWAYS

  • The study aimed to investigate multiple immune checkpoint gene profiles in BLCA to identify potential immunotherapy targets like KRT23.
  • Researchers identified KRT23 as a key target for improving immunotherapy in BLCA.

In recent decades, significant progress has been made in treating bladder cancer (BLCA), particularly with the development of immune checkpoint inhibitors (ICIs). However, most studies have focused on individual ICIs, with limited research addressing the comprehensive gene expression profiles of multiple immune checkpoints. Understanding the broader landscape of immune checkpoint genes is crucial for optimizing immunotherapy strategies and improving patient outcomes.

Dongshan Chen and the team aimed to assess the expression profiles of multiple immune checkpoint genes in BLCA, explore their relationship with the tumor immune microenvironment, and identify key targets for enhancing immunotherapy, with a specific focus on KRT23.

They performed an inclusive analysis using RNA-sequencing profiling data and clinical information from patients with BLCA and normal human bladder samples, sourced from the Cancer Genome Atlas and Gene Expression Omnibus databases.

The data were analyzed to identify differential expression profiles of immune checkpoint genes (ICGs) following consensus clustering analysis. From 526 intersecting differentially expressed genes, LASSO Cox regression analysis was applied to develop an ICG signature, enabling further investigation of immune infiltration and potential therapeutic targets.

Based on the expression of ICGs, patients with BLCA were classified into 3 distinct subtypes, each exhibiting unique phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature was identified as an independent predictor of outcomes in patients with BLCA and was closely associated with immune infiltration, ICG expression levels, and chemotherapy effectiveness.

The study concluded that a systematic and comprehensive analysis of immune checkpoint gene expression led to the establishment of the ICG signature, which revealed significant differences in ICG expression and the tumor immune microenvironment.

This information aids in risk stratification and supports the advancement of precision medicine for BLCA. Furthermore, KRT23 was identified as the most critical model gene, highlighting its potential as a promising target to enhance immunotherapy in patients with BLCA.

The study received no funds.

Source: https://pubmed.ncbi.nlm.nih.gov/39160525/

Chen D, Cao H, Zheng X, et al. (2024). “Immune checkpoint gene signature assesses immune infiltration profiles in bladder cancer and identifies KRT23 as an immunotherapeutic target.” BMC Cancer. 2024;24(1):1024. Published 2024 Aug 19. doi:10.1186/s12885-024-12790-w

Impact of QoL and Optimism on Prognostic Views in mRCC and mBC

KEY TAKEAWAYS

  • The study aimed to evaluate perceptions of treatment outcomes in patients with mRCC and mBC, focusing on the role of optimism and QoL.
  • Most patients with mRCC and mBC had inaccurate views on treatment outcomes, linked to higher QoL and optimism.

Durable complete response rates for metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC) remain low despite advancements in therapy. Palliative care prioritizes life extension and improving quality of life (QoL) rather than a cure.

Hatice Bolek and the team aimed to examine how patients with mRCC and mBC perceive treatment outcomes and how QoL and optimism impact these perceptions.

Between March 15, 2023, and January 15, 2024, researchers conducted a multicenter, cross-sectional online survey targeting patients diagnosed with mRCC and mBC. The survey included structured questions assessing perceptions of disease cure, symptom improvement, daily activity performance, and life extension from treatment.

To measure optimism and QoL, the European Organization for Research and Treatment of Cancer 30.3 QoL questionnaire and the Life Orientation Test were used. The study revealed high optimism and inaccurate beliefs about cure among patients.

About 169 patients participated in the survey, with the majority rating their general health as good (72.2%) and excellent (13.6%). Patients who rated their health as good-excellent had higher median general QoL and optimism scores than those who rated it fair-poor. Overall, 85.2% of patients believed the possibility of a cure was very likely or likely.

Most participants thought treatment would relieve symptoms (30.2% very likely, 49.1% likely), improve daily activity performance (28.4% very likely, 55.6% likely), and extend life (32.5% very likely, 53.3% likely). Patients who responded very likely and likely to these questions had higher QoL and optimism scores than those who responded a little likely or not possible.

The study concluded that most patients with mRCC and mBC held inaccurate beliefs about treatment outcomes. Higher QoL and optimism were linked to greater inaccuracies in these perceptions.

Funding is provided by Roche, Novartis, BMS, Merck, AstraZeneca, Nektar, Johnson &Johnson, Lilly, Amgen, Incyte, Bayer, Yuhan, Henlius, Pfizer, Biontech, Genmab, Beigene, GSK.

Source: https://pubmed.ncbi.nlm.nih.gov/39208383/

Bolek H, Arslan C, Basaran M, et al. (2024). “Perceptions and Expectations: A Study on Prognostic Perception and Quality of Life in Patients With Metastatic Renal and Bladder Cancer.” JCO Glob Oncol. 2024;10:e2400201. doi:10.1200/GO.24.00201

Low HALP Scores Predict Bladder Cancer Recurrence After UTUC

Low HALP Scores Predict Bladder Cancer Recurrence After UTUC

KEY TAKEAWAYS

  • The study aimed to investigate how the HALP score affects pathologic results and bladder cancer recurrence in patients with UTUC.
  • Results showed that lower HALP scores are linked to advanced disease, higher grade, and increased bladder cancer recurrence risk.

Mehmet Yoldas and the team aimed to investigate how the haemoglobin, albumin, lymphocyte, and platelet (HALP) score impacts pathologic outcomes and bladder cancer recurrence (BCR) in patients who underwent surgery for upper urinary tract tumors (UTUCs).

Researchers calculated HALP scores for all patients. They compared demographic data, preoperative blood parameters, pathologic results, and bladder cancer recurrence status between patients with low and high HALP scores.

Results showed that haemoglobin (11.2±2.3 g/dL vs. 12.9±2.4 g/dL), albumin (4.0±0.8 g/dL vs. 4.4±0.9 g/dL), and HALP score (38.2±2.9 vs. 43.4±3.1) were significantly lower in the BCR (+) group compared with the BCR (-) group (P<0.001). The ROC curve indicated an optimal HALP score cut-off point of 40.8. Multivariate analyses demonstrated that the HALP score was effective for Tumour Grade, Tumour Stage, and BCR.

The study concluded that lower HALP scores are associated with more advanced stages, higher-grade pathologic outcomes, and an increased risk of BCR.

No funding information was available.

Source: https://pubmed.ncbi.nlm.nih.gov/39208822/

Yoldas M, Arikan Y, Kuvvet Yoldas T. (2024). “The Effect of the HALP Score on the Development of Bladder Cancer Recurrence in Patients Undergoing Radical Nephroureterectomy for Upper Urinary Tract Tumours.” Der Einfluss des HALP-Scores auf die Entwicklung eines Blasenkrebsrezidivs bei Patienten, die sich einer radikalen Nephroureterektomie aufgrund eines Tumors des oberen Harntrakts unterziehen. Aktuelle Urol. 2024;55(5):452-457. doi:10.1055/a-2359-7990

Enhanced Fuhrman Grading in ccRCC via Radiomics and Spiral CT

KEY TAKEAWAYS

  • The study aimed to investigate the effectiveness of radiomics-based multilayer spiral CT imaging in accurately predicting Fuhrman pathological grading for ccRCC.
  • Researchers noticed that radiomics-based multilayer spiral CT imaging significantly enhances the accuracy of Fuhrman pathological grading in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and accurate pathological grading is essential for prognosis and treatment planning. However, conventional methods using the Fuhrman pathological grading system have significant limitations, often leading to inconsistent and subjective assessments.

Bolin Liu and the team aimed to investigate the potential of using radiomics-based multilayer spiral computed tomography (CT) imaging as a non-invasive, more reliable alternative for predicting Fuhrman pathological grading in ccRCC.

They performed an inclusive retrospective analysis of the clinical data of patients with ccRCC admitted to the hospital from March 2023 to March 2024. The patients were categorized into low-grade (Fuhrman grades I and II) and high-grade (Fuhrman grades III and IV) groups.

Advanced statistical methods, including correlation analysis, receiver operating characteristic (ROC) curves, and the construction of a joint predictive model, were utilized to evaluate the predictive value of radiomics-based multilayer spiral CT imaging indicators for Fuhrman pathological grading in ccRCC. The primary outcome measure focused on determining how effectively these imaging omics indicators could predict the Fuhrman pathological grading in patients with ccRCC.

About 101 patients with ccRCC clinical data were examined, with 56 cases classified as low-grade and 45 cases as high-grade. Notable distinctions were observed in the grey-level co-occurrence matrix (GLCM) features between low and high Fuhrman grading groups, including contrast (0.24 ± 0.08 vs. 0.33 ± 0.09), energy (0.73 ± 0.05 vs. 0.67 ± 0.06), and homogeneity (0.63 ± 0.05 vs. 0.57 ± 0.05) (P < 0.001).

The CT imaging characteristics also demonstrated substantial variation between the low and high Fuhrman grading groups, with enhancement homogeneity (0.34 ± 0.08 vs. 0.26 ± 0.08) and washout half-time (28.57 ± 4.35 vs. 34.72 ± 5.62) showing significant differences (P < 0.001).

Significant correlations were identified between Fuhrman pathological grading and enhancement homogeneity (r = 0.476), washout half-time (r = -0.519), contrast (r = 0.454), energy (r = -0.453), and homogeneity (r = -0.541). The predictive value of these features was highlighted, with a combined imaging genomics model demonstrating an area under the curve of 0.929.

The study concluded that radiomics-based prediction using multilayer spiral CT imaging offers significant potential for accurately predicting Fuhrman pathological grading in clear cell renal cell carcinoma (ccRCC), thereby enhancing the precision of non-invasive diagnostic methods.

No funding information was given.

Source: https://pubmed.ncbi.nlm.nih.gov/39104236/

Liu B, Liu A, Wu Y, et al. (2024). “Enhancing the Efficacy of Radiomics-Based Prediction of Fuhrman Pathological Grading in Renal Clear Cell Carcinoma Using Multilayer Spiral CT Imaging.” Arch Esp Urol. 2024;77(6):674-680. doi:10.56434/j.arch.esp.urol.20247706.92

ERCC Family in Pan-Cancer and ERCC2 in Bladder Cancer

KEY TAKEAWAYS

  • The study aimed to explore ERCC gene expression’s link to prognosis and validate ERCC2’s role in bladder cancer.
  • The ERCC gene family, particularly ERCC2, shows promise as a potential target for cancer treatment due to its association with tumour development and progression.

Single nucleotide polymorphisms (SNPs) within DNA repair genes can disrupt DNA repair mechanisms, potentially causing genetic instability and increasing the risk of cancer, including bladder cancer. The Excision Repair Cross-Complementation (ERCC) family is crucial for nucleotide excision repair, but its impact on bladder cancer prognosis and the immune microenvironment is not yet fully understood.

Siyang Zhang and the team aimed to characterize the ERCC family’s multi-omics profile and investigate its roles in tumour prognosis and the immune microenvironment.

Researchers conducted a bioinformatics analysis using publicly available data from 33 cancer types to examine the association between ERCC gene expression, patient prognosis, and clinical characteristics. The study also included in vitro assays, specifically CCK-8, colony formation, wound healing, and Transwell assays, to validate the role of ERCC2 in bladder cancer.

Analysis revealed a correlation between ERCC expression variations across multiple cancer types, patient prognosis, and the tumour microenvironment (TME). After adjusting for multiple testing using the Benjamini-Hochberg procedure, ERCC expression levels remained significantly correlated with patient prognosis in several cancer types (P< 0.05).

Furthermore, drug sensitivity studies indicated a strong correlation between ERCC expression and the sensitivity of various anticancer drugs. In vitro cell behaviour assays demonstrated that knocking down ERCC2 gene expression significantly inhibited the proliferation, migration, and invasion of bladder cancer cells.

The in-depth analysis of ERCC differential expression and its association with immune-related indicators, the distinctive TME, and patient prognosis has confirmed the potential role of ERCC2 in bladder cancer development and progression. Consequently, the ERCC gene family is anticipated to be a promising candidate for cancer treatment and warrants further exploration.

This work was supported by the Taizhou Science and Technology Program.

Source: https://pubmed.ncbi.nlm.nih.gov/39192988/

Zhang S, Guan Z, Xia Q, et al. (2024). “Bioinformatics analysis of ERCC family in pan-cancer and ERCC2 in bladder cancer.” Front Immunol. 2024;15:1402548. Published 2024 Aug 13. doi:10.3389/fimmu.2024.1402548

APOL6: Biomarker for Immunotherapy Success in Bladder Cancer

KEY TAKEAWAYS

  • The study aimed to assess APOL6 as a biomarker for predicting immunotherapy success in bladder cancer via ferroptosis.
  • Researchers concluded APOL6 may predict immunotherapy success and identified the STAT1/APOL6/GPX4 axis as crucial in BLCA.

Immune checkpoint inhibitors are increasingly used to treat bladder cancer, but effective biomarkers for predicting outcomes remain limited. Ferroptosis, a type of immunogenic cell death, has been shown to improve patient response to these therapies. However, the mechanisms by which ferroptosis enhances immunotherapy effectiveness in bladder cancer are not yet fully understood.

Zhiwei Fan and the team aimed to investigate how ferroptosis influences immunotherapy efficacy in bladder cancer and identify effective biomarkers for predicting treatment outcomes.

Researchers analyzed The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) to identify 2 distinct immunological subtypes. They used these subtypes, along with other public datasets, to identify Apolipoprotein L6 (APOL6) as a potential biomarker for predicting immunotherapy efficacy. They examined APOL6’s immunological correlations and predictive value, and experimentally validated its role in promoting ferroptosis and regulating this process.

The results showed that APOL6 is highly relevant immunologically and marks immunologically active tumors in bladder cancer and other cancers. APOL6 interacts with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) to mediate immunotherapy efficacy through ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1).

The study concluded that APOL6 has potential as a predictive biomarker for immunotherapy success and identified the STAT1/APOL6/GPX4 axis as a key regulatory mechanism in bladder cancer.

This work was supported by National Natural Science Foundation of China (82200819), Natural Science Foundation of Jiangsu Province (BK20220605) and Jiangsu Innovative and Enterpreneurial Talent Programme (JSSCBS20211600).

Source: https://pubmed.ncbi.nlm.nih.gov/39187773/

Fan Z, Liu Y, Wang X, et al. (2024) “APOL6 predicts immunotherapy efficacy of bladder cancer by ferroptosis.” BMC Cancer. 2024;24(1):1046. Published 2024 Aug 26. doi:10.1186/s12885-024-12820-7

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