Role and mechanism of benzo[a]pyrene in the transformation of chronic obstructive pulmonary disease into lung adenocarcinoma

Wang, Lei; Chen, Qi; Liu, Tingting; Bai, Tuya; Zhang, Mengdi; Hu, Yuxia; Li, Jun; Chang, Fuhou

doi:10.1007/s00432-022-04353-y

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…PKHD1L1 has been implicated in or identified as a potential biomarker in several cancers, including but not limited to: thyroid cancer (Zheng et al, 2019), lung adenocarcinoma (Kang et al, 2023; L. Wang et al, 2023), renal cell carcinoma (Yang et al, 2023), skin cutaneous melanoma (Kang et al, 2023), cervical cancer (Zou et al, 2022), squamous cell carcinoma (Song et al, 2021), and breast cancer (Saravia et al, 2019). As described above it has also been identified as a component of the platelet sheddome (Fong et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…PKHD1L1 has been identified as a biomarker or implicated in many cancers (Kang et al, 2023(Kang et al, , 2023Saravia et al, 2019;Song et al, 2021;L. Wang et al, 2023;Yang et al, 2023;Zheng et al, 2019;Zou et al, 2022); and has been linked to schizophrenia (Shang et al, 2024), and anxiety-like traits (Chitre et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…PKHD1L1 is a very large, predominantly extracellular, membrane protein consisting of 4249 amino acids, with a single-pass transmembrane domain and a very short 6-amino acid intracellular cytoplasmic domain. PKHD1L1 has been identified as a biomarker or implicated in many cancers (Kang et al, 2023, 2023; Saravia et al, 2019; Song et al, 2021; L. Wang et al, 2023; Yang et al, 2023; Zheng et al, 2019; Zou et al, 2022); and has been linked to schizophrenia (Shang et al, 2024), and anxiety-like traits (Chitre et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…It is a membrane protein with a single-pass transmembrane domain; however, it is predominantly extracellular, with a very short 5-amino acid intracellular cytoplasmic domain at its C-terminal end. PKHD1L1 has been identified as a potential biomarker or has been implicated in several cancers, including but not limited to: thyroid cancer (Zheng et al, 2019), lung adenocarcinoma (Kang et al, 2023; L. Wang et al, 2023), renal cell carcinoma (Yang et al, 2023), skin cutaneous melanoma (Kang et al, 2023), cervical cancer (Zou et al, 2022), squamous cell carcinoma (Song et al, 2021), and breast cancer (Saravia et al, 2019). Furthermore, rare pathogenic variants of PKHD1L1 have been linked to conditions such as schizophrenia (Shang et al, 2024), in studies involving human subjects, and anxiety-like traits in rodents (Chitre et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

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PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

Strelkova,

Osgood,

Tian

et al. 2024

Preprint

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Sensory hair cells of the cochlea are essential for hearing, relying on the mechanosensitive stereocilia bundle at their apical pole for their function. Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1) is a stereocilia protein required for normal hearing in mice, and for the formation of the transient stereocilia surface coat, expressed during early postnatal development. While the function of the stereocilia coat remains unclear, growing evidence supports PKHD1L1 as a human deafness gene. In this study we carry out in depth characterization of PKHD1L1 expression in mice during development and adulthood, analyze hair-cell bundle morphology and hearing function in aging PKHD1L1-defficient mouse lines, and assess their susceptibility to noise damage. Our findings reveal that PKHD1L1-deficient mice display no disruption to bundle cohesion or tectorial membrane attachment-crown formation during development. However, starting from 6 weeks of age, PKHD1L1-defficient mice display missing stereocilia and disruptions to bundle coherence. Both conditional and constitutive PKHD1L1 knock-out mice develop high-frequency hearing loss progressing to lower frequencies with age. Furthermore, PKHD1L1-deficient mice are susceptible to permanent hearing loss following low-level acoustic overexposure, which typically induces only temporary shifts in hearing thresholds. These results suggest a role for PKHD1L1 in establishing robust sensory hair bundles during development, necessary for maintaining bundle cohesion and function in response to acoustic trauma and aging.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

Strelkova,

Osgood,

Tian

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Future functional studies involving highly conserved full-length PKHD1L1 orthologs and their protein purification would allow for better understanding of various effects such variants might have on the stability of the entire PKHD1L1 extracellular domain, its protein expression and proper localization, which might be linked to the progression and hearing loss severity. Furthermore, studies focused on uncovering the influence of mutations on the structure of the complete PKHD1L1 extracellular domain will help to better understand the role of PKHD1L1 in hearing function and beyond, since the PKHD1L1 has been suggested as a tumor suppressor (Yang et al 2023) and a human cancer biomarker (Kafita et al 2023;Wang et al 2023;Zheng et al 2019).…”

Section: Discussionmentioning

confidence: 99%

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

Redfield,

De-la-Torre,

Zamani

et al. 2023

Preprint

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Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor, given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing.PKHD1L1was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants inPKHD1L1also cause hearing loss in humans.Exome sequencing was performed on DNA of three families segregating autosomal recessive moderate to severe nonsyndromic sensorineural hearing loss. Compound heterozygous missense p.[(Gly129Ser)];p.[(Gly1314Val)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified inPKHD1L1that were predicted to be damaging usingin silicopathogenicity prediction methods.In vitrofunctional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families.In vitrofunctional assessment indicated that both engineered PKHD1L1 mutant p.(Gly129Ser) and p.(Gly1314Val) constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants.In silicomolecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on protein folding and stability and exposed key structural features that might suggest PKHD1L1 protein destabilization.Multiple lines of evidence collectively associatePKHD1L1with nonsyndromic mild-moderate to severe sensorineural hearing loss.PKHD1L1testing in individuals with mild-moderate hearing loss may identify further affected families.

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PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

Redfield,

De-la-Torre,

Zamani

et al. 2024

Hum. Genet.

View full text Add to dashboard Cite

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild–moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild–moderate hearing loss may identify further affected families.

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Role and mechanism of benzo[a]pyrene in the transformation of chronic obstructive pulmonary disease into lung adenocarcinoma

Cited by 7 publications

References 48 publications

PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

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