Contemporary Oncology
eISSN: 1897-4309
ISSN: 1428-2526
Contemporary Oncology/Współczesna Onkologia
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3/2025
vol. 29
 
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abstract:
Original paper

Integrated Mendelian randomization analysis reveals causal relationship between LAMA5 and bladder cancer and its metabolic mechanisms

Renjie Wang
1
,
Zijie Xu
1
,
Zetao Ding
1
,
Jifu Ge
1
,
Qi Pan
1
,
Yigang Zeng
1
,
Fang Zhang
1
,
Weiguang Zhao
2
,
Yin Yang
1
,
Zheng Tang
1
,
Yinyan He
3
,
Zhihong Liu
1

  1. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
  2. Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China
  3. Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China
Contemp Oncol (Pozn) 2025; 29 (3): 287–296
DOI: https://doi.org/10.5114/wo.2025.154061
Online publish date: 2025/09/17
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Introduction:
Previous research has shown that laminin α5 (LAMA5) is es­sential for a variety of biological processes, including cellular adhesion, cell differentiation, migration, and metastasis. However, the role of LAMA5 in bladder cancer (BC) has not been explored before. Therefore, we employed Mendelian randomization (MR) to investigate its involvement and identify underlying metabolic mechanisms.

Material and methods:
Utilizing GWAS data from online databases, we employed integrated MR analyses to investigate the correlations between apoptosis-related genes, metabolites, and BC. We also confirmed the expression of LAMA5 in BC cell lines by qRT-PCR and further explored its cell proliferation, migration, and invasion abilities via the cell viability assay, wound healing, and transwell assays, respectively.

Results:
Our findings suggested that LAMA5 could increase the risks of BC (OR = 1.0013, p < 0.05). Summary-data- based MR (SMR) results also confirmed the associations by cis-eQTLs (both p < 0.05). In in vitro experiments, the expression levels of LAMA5 were identified to be elevated across three different BC cell lines (p < 0.05). Knockdown of LAMA5 led to inhibition of cell proliferation, migration, and invasion, highlighting its potential as a key re­gulatory factor in BC (all p < 0.05). To further shed light on the metabolic mechanisms of LAMA5 involved in BC, MR results showed that LAMA5 was identified as a suppressor of dihydroorotate levels (OR = 0.8946, p < 0.05), which were inversely related to BC risk (OR = 0.9993, p < 0.05).

Conclusions:
LAMA5 was identified as a novel eQTL-mediated oncogenic gene in BC through influencing cell proliferation, migration, and invasion, with its underlying metabolic mechanism involving inhibition of dihydroorotate levels.

keywords:

LAMA5, bladder cancer, Mendelian randomization, metabolites, oncogenesis
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