Research ArticleExperimental Studies
Open Access

HOOK3 Amplification in Bladder Urothelial Carcinoma: Insights from Gene Expression and Survival Analysis

JABER H. JARADAT, YASSINE ALAMI IDRISSI and ANWAAR SAEED
Anticancer Research December 2024, 44 (12) 5175-5185; DOI: https://doi.org/10.21873/anticanres.17343

Abstract

Background/Aim: Bladder urothelial carcinoma (BUC) poses a significant health challenge, ranking as the fourth most common cancer among men in the United States, with a mortality rate of approximately 20%. Genetic abnormalities such as mutations in the telomerase reverse transcriptase (TERT) gene and loss of heterozygosity (LOH) on chromosome 9 are commonly observed in BUC; however, many genes involved remain unidentified. This study aimed to explore the role of HOOK3 in BUC and its impact on survival. Materials and Methods: Using data from The Cancer Genome Atlas (TCGA) and cBioPortal, we performed differential gene expression and survival analyses to compare the patients with and without HOOK3 amplification. Results: Our findings revealed that 2.2% of genes were up-regulated and 5.3% down-regulated in the HOOK3-amplified group. These changes suggest that HOOK3 amplification is linked to distinct gene expression patterns, with a higher proportion of down-regulated genes. Pathway enrichment related to chromatin remodeling, ion transport, and mitochondrial function suggests that HOOK3 may promote genomic stability and transcriptional regulation, contributing to tumor suppression. The involvement of mitochondrial and ribosomal pathways in protein synthesis and chromosome segregation may also protect against chromosomal abnormalities and uncontrolled cell growth. HOOK3 amplification appears to correlate with improved patient survival. Conclusion: These results suggest a potential protective role of HOOK3 amplification in BUC. Further research is needed to explore the underlying mechanisms and their therapeutic potential for reducing BUC-related mortality.

Key Words:

The urothelium, traditionally classified as a transitional epithelium, displays characteristics between stratified columnar and stratified squamous epithelia, adapting its morphology based on bladder distension. While historically referred to as a transitional epithelium, debate exists over whether it is truly stratified or pseudostratified, and the term “urothelium” is now preferred. The urothelium is composed of three layers: the superficial, intermediate, and basal layers, and lines the entire urogenital tract (UGT) from the renal pelvis to the proximal urethra (1). Although urothelial carcinoma can develop in any part of the UGT, 90% of cases originate from the bladder. Debate persists over the origin of bladder cancer stem cells, and ongoing research aims to clarify these pathways (2, 3).

According to the American Cancer Society’s 2024 statistics, bladder urothelial carcinoma (BUC) accounts for 83,190 new cases annually in the US, making it the fourth most common cancer in men. It is approximately five times more prevalent in men than in women. In patients with metastatic urothelial carcinoma, the standard first-line treatment is platinum-based combination therapy, typically gemcitabine and cisplatin or the methotrexate, vinblastine, doxorubicin, and cisplatin regimen, followed by avelumab maintenance therapy for those achieving stable disease. For patients who do not achieve stability, various treatment options are now available, including PD-L1-targeting immunotherapies, tyrosine kinase inhibitors, and antibody-drug conjugates (4). Wong et al. demonstrated that patients ineligible for these newer treatments had better overall survival with subsequent platinum-based chemotherapy compared to non-platinum regimens (4). Additionally, Vassiliou et al. highlighted the use of radiotherapy as palliative care, effectively improving hematuria and skeletal pain in metastatic urothelial carcinoma patients (5). Despite these advances in treatment, about 20% of patients die from BUC, highlighting the need for further research to improve outcomes (6).

Genomic studies have emerged as a valuable tool in understanding cancer development and identifying potential therapeutic targets. In BUC, several key genetic mutations have been identified. For example, telomerase reverse transcriptase (TERT) mutations have been found in 70% of cases, according to a 2013 study in Barcelona. Other consistent abnormalities include loss of heterozygosity (LOH) in chromosome 9 and mutations in genes, such as TP53 and HRAS, which are also implicated in other cancers. Many genetic factors in BUC remain unexplored, warranting further research (7).

The human hook microtubule-tethering protein (HOOK) family plays a crucial role in intracellular transport by linking organelles or vesicles to the microtubule network. These proteins facilitate the movement of cellular cargo, such as endosomes and lysosomes, by acting as adaptors for the dynein motor complex. Structurally, HOOK proteins have an N-terminal microtubule-binding domain, a central coiled-coil domain for dimerization, and a C-terminal cargo-binding domain. There are three main HOOK proteins – HOOK1, HOOK2, and HOOK3 – each contributing to different cellular functions, such as spermatogenesis, centrosome positioning, and endocytic trafficking, respectively. Notably, HOOK3 plays a key role in linking vesicular transport to the Golgi apparatus (8–13). While HOOK proteins have been linked to intracellular transport and neurodegenerative disorders, recent studies suggest that they may also play a pivotal role in cancer. Specifically, HOOK3 has garnered attention due to its strong correlation with genomic instability in cancer. In prostate cancer, overexpression of HOOK3 has been associated with adverse tumor characteristics, including advanced stage, high Gleason grade, nodal metastasis, and PSA recurrence. Moreover, elevated HOOK3 expression has been observed across various cancers, including prostate cancer, colorectal cancer, endometrial cancer, glioma, lymphoma, and thyroid cancer, suggesting its involvement in oncogenesis (14). In this study, we investigated the role of the HOOK3 gene in BUC by analyzing survival and expression patterns.

Materials and Methods

Data collection and processing. The Cancer Genome Atlas (TCGA) database (15,16) was used to gather gene expression data via cBioPortal (https://www.cbioportal.org/) (17). Specifically, data were obtained for 412 patients from the Bladder Urothelial Carcinoma (TCGA, Firehose Legacy) dataset. Among these patients, HOOK3 amplification was observed in only 24 cases by copy number alteration (CAN), as determined by cBioportal. Consequently, the data were categorized into two groups: patients with normal HOOK3 gene expression and those with amplified HOOK3 expression.

Differential gene expression analysis. Differential gene expression analysis was performed using the DESeq2 package in R (18, 19). An adjusted p-value <0.05 was used for the analysis. Prior to executing the DESeq2 pipeline, a quality control step was applied by excluding any gene whose row sums were less than 10, ensuring the reliability of the data. Additionally, the contrast level for the analysis was set to patients without HOOK3 amplification, allowing comparisons to be made relative to this baseline.

Gene ontology and gene set enrichment analysis. Gene Ontology (GO) and Gene Set Enrichment Analyses (GSEA) were conducted using the ClusterProfiler package in R, with plots generated through the enrichplot package (20, 21). Enrichment analysis of differentially expressed genes within the merged dataset was carried out with clusterProfiler, focusing on GO terms categorized under biological processes (BP), cellular components (CC), and molecular functions (MF).

Survival analysis. Kaplan-Meier survival analysis and log-rank test were conducted using the Survival package in R, while survival curves were visualized using the Survminer package (22, 23).

Results

Descriptive. Data from 412 patients were analyzed and are summarized in Table I. A scatter plot illustrating the gene mutations in relation to the fraction of the altered genome is shown in Figure 1.

View this table:
Table I.

Characteristics of patients with HOOK3 gene amplification and non-amplified HOOK3 gene in bladder carcinoma.

Figure 1.
Figure 1.

Scatter plot of the fraction of genome altered and mutation count. (A) Scatter plot of the fraction of genome altered. Samples of the whole dataset are plotted. No significant correlation can be seen between the fraction of genome altered and mutation count. (B) Fraction of genome altered vs. mutation count for samples with HOOK3 amplification.

Differential gene expression. RNA sequencing data from 408 patients were downloaded, with 24 sequences corresponding to patients with amplified HOOK3 gene. After cleaning the data, 406 RNA sequences were retained for differential gene expression analysis. The dataset initially contained 20,505 genes, but following quality control, where genes with counts below 10 were filtered out, 20,179 genes were retained. Among these, 445 genes (2.2%) were up-regulated, and 1,066 genes (5.3%) were down-regulated (Figure 2), and the log2 fold change was set to 0 and adjusted p-value was set to 0.05. The median log-fold change was −0.0623, with values ranging from −0.3371 to 0.1247; no outliers were identified. The top 10 up-regulated genes, ranked by log2 fold change, were KAAG1, DAW1, SULT1B1, SELL, PNMT, DCDC2, SLC26A4-AS1, TMEFF2, SLC6A3, and PRSS3, which exhibited the highest levels of increased expression. Conversely, the ten most down-regulated genes were KRT75, KLK9, ADIPOQ, KRT14, BNC1, PI3, KLK8, KRT6B, ALB, and KLK5, showing the greatest decrease in expression levels.

Figure 2.
Figure 2.

Volcano plot of differentially expressed genes (DEGs) in patients with HOOK3 gene amplification. Up-regulated and down-regulated genes are shown in the right and left, respectively. Genes with p-Value of 10e-5 or greater are above the dotted line.

Gene ontology and gene enrichment analysis. GO analysis of genes with a log2-fold change greater than 0.5 revealed significant enrichment in various BPs, MFs, and CCs. The most enriched BP was “protein-DNA complex assembly”, while the most enriched MF was “metal ion transmembrane transporter activity”, and the most enriched CC was the “nucleosome” (Figure 3). Conversely, for genes with a log fold change less than −0.5, the least enriched BP in patients with HOOK3 gene amplification was “epidermis development”, while the least enriched MF was “glycosaminoglycan binding”, and the least enriched CC was “collagen-containing extracellular matrix”.

Figure 3.
Figure 3.

Barplots of gene ontology terms. (A) Biological processes (BP) with log fold change greater than 0.5. (B) BP with log fold change less than −0.5. (C) Molecular function (MF) with log fold change greater than 0.5. (D) MF with log fold change less than −0.5. (E) Cellular components (CC) with log fold change greater than 0.5. (F) CC with log fold change less than −0.5.

Additionally, GSEA was conducted, highlighting various pathways related to HOOK3 gene amplification (Figure 4). Among the top 10 enriched BPs in the HOOK3 gene amplified group were pathways linked to mitochondrial function and cellular division. Key processes, such as “mitochondrial translation” and “mitochondrial gene expression”, underscore HOOK3 role in mitochondrial protein synthesis and regulation. Other enriched pathways include “ribosome assembly” and “ribosome biogenesis”, both crucial for protein synthesis and pathways related to chromosome dynamics and cell cycle regulation, such as “regulation of chromosome separation”, “mitotic sister chromatid separation”, “chromosome separation”, “mitotic spindle assembly checkpoint signaling” and “spindle assembly checkpoint signaling”. These results highlight the importance of cell cycle and protein synthesis processes in HOOK3 amplification. In contrast, the top ten BP in patients without HOOK3 amplification were more related to immune defense and epidermal development. Additionally, pathways related to intermediate filament structures, such as “intermediate filament-based process”, “intermediate filament cytoskeleton organization” and “intermediate filament organization” were enriched in this group.

Figure 4.
Figure 4.

Enrichment plots of gene sets in biological processes (BP). Genes from the top ten enriched genes in BP, related to mitochondrial and cellular division are presented. The x-axis represents the ordered genes by the Wald statistic of the DESeq2 function. (A) represents the gene sets enrichment related to mitochondrial gene expression and translation. (B) represents the gene sets enrichment of mitotic functions.

In the HOOK3- amplified group, the top 10 enriched MFs reflected key roles in chromatin structure, ribosomal activity, and RNA polymerase function. Additionally, several RNA polymerase-related functions were enriched, highlighting the importance of the transcriptional machinery.

Other significant functions involved gene regulation, chromosome remodeling, and transcriptional control. In contrast, patients without HOOK3 amplification showed enrichment for various enzyme activities and structural roles. These included “endopeptidase inhibitor activity”, “peptidase inhibitor activity”, and several serine related processes like “serine-type endopeptidase activity”, “serine-type endopeptidase inhibitor activity” and “serine hydrolase activity”. Structural roles such as “structural constituent of cytoskeleton” and “structural constituent of skin epidermis” were also prominent, alongside signaling functions like “MAP kinase phosphatase activity” and “chemokine receptor binding”.

In the context of cellular components, the top ten enriched gene sets in patients with HOOK3 gene amplification underscore critical roles in nucleosome and ribosomal functions. Key gene sets are involved in DNA packaging and protein synthesis. Additional enriched sets, such as “ribosomal subunit”, “organellar ribosome”, and “mitochondrial ribosome” further emphasize essential roles in cellular translation. Moreover, the enrichment of the “spliceosomal tri-snRNP complex” and “U4/U6 ´ U5 tri-snRNP complex” highlights the importance of mRNA splicing, whereas “CENP-A containing nucleosome” and “CENP-A containing chromatin” suggest significant involvement in chromosome organization and segregation. In contrast, the top ten CC enriched gene sets in patients without HOOK3 gene amplification were predominantly related to extracellular and cytoskeletal components which played roles in cellular signaling and storage. A hierarchical tree plot visualizing the relationships between enriched GO terms is shown in Figure 5.

Figure 5.
Figure 5.

Hierarchical clustering of enriched terms, in patients with HOOK3 gene amplification, presented using a tree plot generated from pairwise similarity matrices. The tree plot shows the relationships between enriched terms, highlighting clusters of biologically similar terms.

Survival. In this survival analysis, we assessed overall survival (OS) and disease-free survival (DFS) based on gene amplification status, comparing the amplified (AMP) group to the non-amplified (NAMP) group. For OS, the AMP group consisted of 23 patients with 5 events, while the NAMP group included 379 patients with 170 events. The median survival for the AMP group could not be determined, whereas the median survival for the NAMP group was 33 months [95% confidence interval (CI)=26.1-46.8 months]. A chi-square test for OS yielded a value of 3.9 with one degree of freedom and a p-Value of 0.049, suggesting a statistically significant difference between the groups and indicating longer survival in the AMP group (see Figure 6).

Figure 6.
Figure 6.

Kaplan Meier (KM) curves with p-values from the log-rank test. The dotted lines represent median survival. Figure 6A shows the overall survival curve, while Figure 6B shows the disease-free survival.

For DFS, the AMP group had 20 patients with 5 events, while the NAMP group included 296 patients with 134 events. The median DFS in the AMP group could not be calculated, with an upper confidence interval limit of 51.4 months. In contrast, the median DFS for the NAMP group was 29.8 months (95% CI=25.0-54.8 months). A chi-square test for DFS produced a value of 3.3 with one degree of freedom and a p-value of 0.07, indicating no statistically significant difference in DFS between the AMP and NAMP groups.

Discussion

In this study, we investigated the role of the HOOK3 gene in bladder urothelial carcinoma, where differential gene expression analysis revealed significant changes, with a higher proportion of down-regulated genes in the HOOK3-amplified group. Pathways related to chromatin remodeling, ion transport, and mitochondrial function were among the most enriched in this group, suggesting their potential roles in tumor suppression and cellular maintenance. Specifically, enrichment in processes such as protein-DNA complex assembly, metal ion transmembrane transporter activity, and chromatin-related components indicates that HOOK3 may contribute to genomic stability, transcription regulation, and proper cell cycle progression, collectively reducing the likelihood of uncontrolled cell proliferation.

In the context of oncogenesis, the amplified group also showed significant enrichment in mitochondrial and ribosomal pathways, emphasizing the importance of protein synthesis, mitochondrial translation, and chromosome segregation. These processes are critical for cellular energy production and division, and their dysregulation is commonly implicated in cancer progression. Pathways such as “mitotic spindle assembly checkpoint signaling” and “chromosome separation” further highlight HOOK3’s role in preventing chromosomal abnormalities that promote tumorigenesis.

Conversely, the non-amplified group displayed enrichment in pathways related to immune defense, epidermal development, and intermediate filament structures, suggesting distinct cellular responses between the two groups. These findings support the hypothesis that Hook3 amplification may confer a protective effect by preserving key cellular functions related to genome integrity and protein synthesis, potentially explaining the improved overall survival seen in patients with HOOK3 amplification in our study. However, further research is necessary to clarify these mechanistic links and their potential as therapeutic targets in BUC.

Our findings align with previous research that highlights HOOK3’s role in other cancer types. For instance, Yang et al. demonstrated that HOOK3 plays a pivotal role in inhibiting gastric cancer growth and invasion by regulating the SP1/VEGFA pathway. Suppression of HOOK3 led to increased VEGFA expression and tumor progression, while its overexpression reduced tumor growth, migration, and invasion, correlating with improved survival in gastric cancer (24). This suggests that HOOK3 amplification may similarly have a protective effect in BUC, contributing to enhanced patient survival.

The mechanisms underlying HOOK3’s anticancer activities are complex. Jin et al. used miR-496 to knock down Hook3 expression and found that its down-regulation prevented apoptosis in cardiomyocytes by activating the PI3K/Akt/mTOR pathway. Conversely, HOOK3 overexpression induced apoptosis, reducing cancer cell proliferation by inhibiting this pathway (25). Additionally, Wortzel et al. identified HOOK3 as a negative regulator of Golgi apparatus destabilization, which impedes mitosis progression, providing another protective mechanism against cancer progression (26). This dual functionality of promoting apoptosis while regulating mitosis highlights Hook3’s complex role in tumor dynamics.

However, other studies have reported pro-cancerous effects of HOOK3. For example, Melling et al. found that HOOK3 overexpression in prostate cancer was associated with adverse tumor characteristics, including advanced stage, high Gleason grade, nodal metastasis, and PSA recurrence, correlating negatively with survival outcomes (14). Similarly, Zhang et al. identified the HOOK3-FGFR1 fusion gene in 8p11 myeloproliferative syndrome, activating the NF-kappaβ pathway and potentially contributing to acute myeloid leukemia (27). Another study by Sun et al. showed that midazolam increased cisplatin sensitivity in cisplatin-resistant non-small cell lung cancer by indirectly reducing HOOK3 expression via miR-194-5p up-regulation, which targets HOOK3’s 3′ untranslated region (28). Ciampi et al. also described a novel RET/PTC rearrangement in papillary thyroid cancer involving RET/HOOK3, resulting in tumor formation in a mouse model, demonstrating its oncogenic potential (29). These findings indicate that HOOK3 can exhibit either protective or detrimental effects depending on the cancer type and involved molecular pathways, warranting further investigation into its precise mechanisms.

However, this study has several limitations. Firstly, the sample size of patients with HOOK3 amplification was relatively small (24 out of 412), which may restrict the generalizability of the findings. Additionally, reliance on the TCGA data means that the results may not fully capture the heterogeneity of BUC across diverse populations. Furthermore, our analysis focused exclusively on gene expression data, without considering post-transcriptional modifications or protein-level changes that could also influence cancer progression.

Conclusion

Our research underscores the potential significance of HOOK3 amplification in BUC, demonstrating its association with improved patient survival. This suggests that HOOK3 may play a beneficial role in disease progression by modulating key survival pathways. While these results are promising, further studies are necessary to elucidate the precise mechanisms through which HOOK3 affects BUC outcomes. Our findings lay the groundwork for future research into the role of HOOK3 in cancer biology and highlight the importance of genetic factors in understanding and managing bladder urothelial carcinoma.

Acknowledgements

The results and data presented here are in whole based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Footnotes

  • Authors’ Contributions

    Conceptualization: JHJ and AS; Resources: JHJ, YAI, and AS; Analysis: JHJ; Writing – original draft: JHJ and YAI; Review and editing: JHJ, AS, and YAI; Supervision: AS. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    The Authors have no support or funding to report.

  • Received September 17, 2024.
  • Revision received September 26, 2024.
  • Accepted October 16, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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HOOK3 Amplification in Bladder Urothelial Carcinoma: Insights from Gene Expression and Survival Analysis
JABER H. JARADAT, YASSINE ALAMI IDRISSI, ANWAAR SAEED
Anticancer Research Dec 2024, 44 (12) 5175-5185; DOI: 10.21873/anticanres.17343
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