CERKL is upregulated in cutaneous squamous cell carcinoma and maintains cellular sphingolipids and resistance to oxidative stress*

Meyer, Jason M.; Lee, E; Celli, Anna; Park, Kyungho; Cho, R; Lambert, W. Clark; Pitchford, M.; Gordon, M.; Tsai, Kenneth Y.; Cleaver, James E.; Arron, Sarah T.; Mauro, Theodora M.

doi:10.1111/bjd.19753

Cited by 6 publications

(6 citation statements)

References 19 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, mutations in the CERKL gene have only been associated with retinal dystrophies, such as retinitis pigmentosa and cone-rod dystrophy [ 5 , 20 ], although recent studies have shown its potential role in other not-related-to-retina tissues and pathologies [ 14 , 15 ]. Although CERKL specific function still remains undetermined, there are several studies with evidence suggesting it plays a crucial role regulating homeostasis and survival of photoreceptors and retinal neurons acting as a resilience gene against apoptosis and regulating mitochondrial health in front of oxidative stress [ 7 , 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, although CERKL plays a protective role against oxidative stress in different tissues such as epidermis and brain [ 14 , 15 ], CERKL mutations have been reported to solely affect the retina so far. Each tissue is especially vulnerable to different stress events and relies on distinct resilience molecular mechanisms [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, overexpression of CERKL protects retinal pigment epithelium from oxidative stress through the regulation of mitochondrial dynamics [ 13 ]. Moreover, CERKL enhances the survival of cutaneous squamous cell carcinoma challenged by oxidative stress [ 14 ]. CERKL overexpression has been also recently shown to alleviate the ischemia reperfusion induced nervous system injury by regulating SIRT1/PINK1/Parkin pathway [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons

García-Arroyo

Marfany

Mirra

2022

IJMS

View full text Add to dashboard Cite

Mutations in the Ceramide Kinase-Like (CERKL) gene cause retinal dystrophies, characterized by progressive degeneration of retinal neurons, which eventually lead to vision loss. Among other functions, CERKL is involved in the regulation of autophagy, mitochondrial dynamics, and metabolism in the retina. However, CERKL is nearly ubiquitously expressed, and it has been recently described to play a protective role against brain injury. Here we show that Cerkl is expressed in the hippocampus, and we use mouse hippocampal neurons to explore the impact of either overexpression or depletion of CERKL on mitochondrial trafficking and dynamics along axons. We describe that a pool of CERKL localizes at mitochondria in hippocampal axons. Importantly, the depletion of CERKL in the CerklKD/KO mouse model is associated with changes in the expression of fusion/fission molecular regulators, induces mitochondrial fragmentation, and impairs axonal mitochondrial trafficking. Our findings highlight the role of CERKL, a retinal dystrophy gene, in the regulation of mitochondrial health and homeostasis in central nervous system anatomic structures other than the retina.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons

García-Arroyo

Marfany

Mirra

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…In this issue of the BJD , Meyer et al 7 . investigated CERKL in squamous cell carcinoma and its role in protecting against apoptosis driven by oxidative damage.…”

mentioning

confidence: 99%

Ceramide kinase‐like protein, ‘the kinase that isn’t’, finds a role in skin cancer stress relief

O'Shaughnessy

2021

Br J Dermatol

View full text Add to dashboard Cite

How to select outcome measurement instruments for outcomes included in a "Core Outcome Set" -a practical guideline. Trials 2016; 17:449. 3 Thomas KS, Apfelbacher CA, Chalmers JR et al. Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting. Br J Dermatol 2021; 185:139-46. 4 Howells LM, Chalmers JR, Gran S et al. Development and initial testing of a new instrument to measure the experience of eczema control in adults and children: Recap of atopic eczema (RECAP). Br J Dermatol 2020; 183:524-36. 5 Simpson E, Eckert L, Gadkari A et al. Validation of the Atopic Dermatitis Control Tool (ADCT©) using a longitudinal survey of biologic-treated patients with atopic dermatitis.

show abstract

“…Whilst the remaining upregulated mRNAs have not previously been shown to be upregulated specifically in SBTs, it is not surprising that these have been previously associated with the development of other cancers. For example, CFAP276 expression is associated with positive prognosis of renal clear cell carcinoma [582], GAS2L2 is mutated in cancer but functional significance is unknown [583], DNAH3 [584] and FAM81B [585] are upregulated in breast cancer and CERKL in cutaneous squamous cell carcinoma is associated with decreased ability to respond to oxidative stress [586].…”

Section: Specific Mirna Tissue Transcriptional Markers Of Serous Bord...mentioning

confidence: 99%

Identifying Novel Candidate Biomarkers of Early Epithelial Ovarian Cancer

Sczelecki¹

View full text Add to dashboard Cite

Ovarian cancer (OC) is the fifth leading cause of cancer deaths in women, and is the most lethal gynaecological cancer worldwide, with the most common subtype being epithelial OC (EOC). The asymptomatic nature and limited understanding of early disease hampers research into early-stage OC and culminates in diagnostic methods only capable of detecting malignant markers of OC. Therefore, there is an urgent need for biomarkers of early-stage OC to be identified. The first aim of this thesis was to validate a unique mouse model of early OC development. The homozygous Fanconi anemia complementation group D2 knock-out mouse (Fancd2-/-) develops multiple ovarian tumor phenotypes in a sequential manner as they age. Our group previously identified by immunohistochemistry the purported initiating precursor cells, termed ‘sex cords’, that are hypothesised to progress into EOC in this model. To genetically validate this hypothesis, the sex cords, a late-stage tumor phenotype (tubulostromal adenoma), and Fancd2 wild-type (Fancd2+/+) granulosa cell and stromal controls, were isolated by laser-capture microdissection for downstream genetic investigation. Multiplexed gene expression analyses of ~ 90 selected genes were performed using the Genome Lab GeXP Genetic Analysis System (GeXP). Principal component analyses and unbiased hierarchical clustering of the resultant gene expression data determined that the gene signature profiles within sex cords and tubulostromal adenoma samples indeed clustered together genetically confirming the identity of a precursor lesion in this mouse model. Furthermore, key epithelial OC markers included in the GeXP assay (Pax8, Cdh1 and Muc16) were expressed in both the sex cords and tubulostromal adenoma demonstrating neoplastic transformation was already occurring in the precursor lesion. Despite confirmation of the identity and developmental origin of the precursor lesion (sex cords), an in-depth understanding of the model was limited due to restricted numbers of genes able to be investigated using the GeXP assay, thus unique markers of the precursor lesion were not identified. Therefore, the second aim of this thesis was to comprehensively investigate the genetic signature of the Fancd2-/- model via total and small RNA sequencing of micro-dissected cells of the sex cords, tubulostromal adenomas and the equivalent Fancd2+/+ controls. Sequencing results of matched messenger (m) RNAs and micro (mi) RNA expression in micro-dissected tissue of the phenotypes of interest provided novel information about the development of early EOC and unique transcriptional markers, namely upregulated Brinp2, Slc6a7, Smpd3, Grin2b, Grik4, AW55198, Lrp11 and Mro mRNAs and downregulated miR-122/b-5p, miR-129-5p, miR-138-5p, miR-465a/b/-3p, miR-465c-3p/5p, miR-500-3p and miR-129b-3p miRNAs of the sex cord phenotype through differential gene expression analysis. Whilst tissue markers of EOC are relevant as biomarkers of EOC, the location of the ovaries within the peritoneum prevents their diagnostic implementation without surgical intervention. To circumvent this limitation, liquid biopsy has become paramount for OC diagnosis. However, the detection of early biomarkers of EOC in humans is ultimately hampered by their low systemic concentration and the presence of circulating factors from all other organ systems. Therefore, to bypass detection limitations within systemic circulation, the next aim of this thesis was to leverage the established Fancd2-/- model of early EOC to provide proof of concept that secreted miRNA encapsulated into extracellular vesicles (EV) secreted from the precursor lesion (i.e., sex cords) could be detected in conditioned media from ovary explant culture. Performing RNA sequencing from EV-derived small RNAs isolated from conditioned culture medium resulted in the identification of five common upregulated secreted EV miRNAs in Fancd2-/- mouse ovaries that had sex cords or tubulostromal adenomas present, compared to their age-matched Fancd2+/+ counterparts. Additionally, the small RNA sequencing data of EVs was compared to the sequencing data of the micro-dissected sex cords and tubulostromal adenomas and these identical five miRNAs were also significantly upregulated as compared to the control group. This suggests that these five secreted EV miRNAs (miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-429-3p and miR-375-3p) originate from the sex cord and tubulostromal adenoma cells and therefore provided proof-of-concept that small transformational changes such as the development of a precursor lesion can be detected within secreted EVs. The final aim of this thesis was to determine whether the methodologies adopted for early candidate biomarker discovery in a murine model can be applied to human biopsy specimens and subsequently the relevance of the Fancd2-/- model for identifying novel biomarkers for human EOC. Two serous subtypes of human EOC, early low-grade serous borderline tumours (SBT; as an early phenotype) and high-grade serous ovarian cancer (HGSOC; as a late malignant phenotype) were selected for study. SBT and HGSOC specimens were prepared for matched micro-dissected neoplastic epithelial cells and explant cultures. Total and small RNA sequencing of micro-dissected tissue and small RNA sequencing of EVs from explant cultures were performed as per the mouse studies. This sequencing data resulted in the identification of SBT tissue-specific mRNA and miRNA markers as well as SBT-secreted miRNA markers. Remarkably, comparing the human and mouse sequencing data revealed an overlap in differentially expressed genes between the SBT, HGSOC, sex cords, and tubulostromal adenomas, pertaining to key epithelial markers of EOC (Muc16, Cdh1, Krt7, Krt19, Epcam) and the five secreted EV miRNAs firstly described in the murine studies. This provides strong evidence that these novel candidate biomarkers are relevant to early human EOC. Overall, the results from this thesis confirmed the relevance of the Fancd2 model for human OC investigation and identified novel candidate biomarkers of early EOC that may be applied to both the mouse model and human ovarian cancer.

show abstract

CERKL is upregulated in cutaneous squamous cell carcinoma and maintains cellular sphingolipids and resistance to oxidative stress*

Cited by 6 publications

References 19 publications

CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons

CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons

Ceramide kinase‐like protein, ‘the kinase that isn’t’, finds a role in skin cancer stress relief

Identifying Novel Candidate Biomarkers of Early Epithelial Ovarian Cancer

Contact Info

Product

Resources

About