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Genome Biology Mar 2021Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization....
BACKGROUND
Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear.
RESULTS
Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma.
CONCLUSION
We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
Topics: Acetylation; Adenosine; Cell Line, Tumor; Cell Transformation, Neoplastic; Epigenesis, Genetic; Eye Neoplasms; Gene Expression Regulation, Neoplastic; Histones; Humans; Melanoma; Models, Biological; Oncogenes; Period Circadian Proteins; RNA, Messenger; RNA-Binding Proteins; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 33726814
DOI: 10.1186/s13059-021-02308-z -
International Journal of Molecular... Jun 2021Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as... (Review)
Review
Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.
Topics: Animals; Genetic Predisposition to Disease; Humans; Melanoma; Risk Factors; Signal Transduction; Skin; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 34203771
DOI: 10.3390/ijms22126395 -
Indian Journal of Ophthalmology Dec 2019Tumors of the conjunctiva and cornea comprise a large and varied spectrum of conditions. These tumors are grouped into two major categories of congenital and acquired... (Review)
Review
Tumors of the conjunctiva and cornea comprise a large and varied spectrum of conditions. These tumors are grouped into two major categories of congenital and acquired lesions. The acquired lesions are further subdivided based on origin of the mass into surface epithelial, melanocytic, vascular, fibrous, neural, histiocytic, myxoid, myogenic, lipomatous, lymphoid, leukemic, metastatic and secondary tumors. Melanocytic lesions include nevus, racial melanosis, primary acquired melanosis, melanoma, and other ocular surface conditions like ocular melanocytosis and secondary pigmentary deposition. The most frequent nonmelanocytic neoplastic lesions include squamous cell carcinoma and lymphoma, both of which have typical features appreciated on clinical examination. The caruncle displays a slightly different array of tumors compared to those elsewhere on the conjunctiva, as nevus and papilloma are most common, but oncocytoma and sebaceous gland hyperplasia, adenoma, and carcinoma can be found. In this report, we provide clinical description and illustration of the many conjunctival and corneal tumors and we discuss tumor management.
Topics: Conjunctival Neoplasms; Corneal Diseases; Eye Neoplasms; Humans
PubMed: 31755426
DOI: 10.4103/ijo.IJO_2040_19 -
Human Vaccines & Immunotherapeutics May 2022Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor because compared to other cancers it usually presents a well-expressed... (Review)
Review
Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor because compared to other cancers it usually presents a well-expressed lymphoid infiltration. The aim of this paper is to perform a multidisciplinary comprehensive review of the evidence available about the combination of radiotherapy and immunotherapy for melanoma. Radiation, in fact, can increase tumor antigens visibility and promote priming of T cells but can also exert immunosuppressive action on tumor microenvironment. Combining radiotherapy with immunotherapy provides an opportunity to increase immunostimulatory potential of radiation. We therefore provide the latest clinical evidence about radiobiological rationale, radiotherapy techniques, timing, and role both in advanced and systemic disease (with a special focus on ocular melanoma and brain, liver, and bone metastases) with a particular attention also in geriatric patients. The combination of immunotherapy and radiotherapy seems to be a safe therapeutic option, supported by a clear biological rationale, even though the available data confirm that radiotherapy is employed more for metastatic than for non-metastatic disease. Such a combination shows promising results in terms of survival outcomes; however, further studies, hopefully prospective, are needed to confirm such evidence.
Topics: Aged; Combined Modality Therapy; Humans; Immunologic Factors; Immunotherapy; Melanoma; Prospective Studies; Radiotherapy; Tumor Microenvironment
PubMed: 33847208
DOI: 10.1080/21645515.2021.1903827 -
Progress in Retinal and Eye Research Sep 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are... (Review)
Review
Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
Topics: Clinical Trials, Phase III as Topic; Humans; Liver Neoplasms; Melanoma; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retrospective Studies; Uveal Neoplasms
PubMed: 34999237
DOI: 10.1016/j.preteyeres.2022.101041 -
Surgical Pathology Clinics Jun 2021PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen expressed in cutaneous and ocular melanomas and some other malignant neoplasms,... (Review)
Review
PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen expressed in cutaneous and ocular melanomas and some other malignant neoplasms, while its expression in normal tissue and benign tumors is limited. Detection of PRAME protein expression by immunohistochemistry in a cohort of 400 melanocytic tumors showed diffuse nuclear immunoreactivity for PRAME in most metastatic and primary melanomas. In contrast, most nevi were negative for PRAME or showed nondiffuse immunoreactivity. The difference in the extent of immunoreactivity for PRAME in unambiguous melanocytic tumors prompted the study of PRAME as an ancillary tool for evaluating melanocytic lesions in more challenging scenarios.
Topics: Antigens, Neoplasm; Humans; Immunohistochemistry; Melanoma; Skin Neoplasms
PubMed: 34023098
DOI: 10.1016/j.path.2021.01.001 -
Archives of Pathology & Laboratory... May 2022Conjunctival melanocytic lesions consist of a variety of neoplastic and nonneoplastic conditions. These include benign processes such as primary intraepithelial...
CONTEXT.—
Conjunctival melanocytic lesions consist of a variety of neoplastic and nonneoplastic conditions. These include benign processes such as primary intraepithelial hypermelanosis and melanocytic hyperplasia, secondary forms of intraepithelial hypermelanosis and melanocytic hyperplasia, melanocytic nevi, melanocytic proliferations with malignant potential, and melanoma.
OBJECTIVE.—
To provide a concise yet comprehensive resource regarding the histopathologic diagnosis of conjunctival melanocytic lesions. We aim to detail and clarify the numerous classification schemes that exist for junctional melanocytic proliferations of the conjunctiva (known as primary acquired melanosis or PAM; also termed conjunctival melanocytic intraepithelial neoplasia or C-MIN). Although not uniformly adopted, C-MIN is classified by using a numeric system based on a defined set of criteria. A less complex scheme (conjunctival melanocytic intraepithelial lesion or CMIL) has recently been proposed by the World Health Organization. Additionally, we aim to update the reader regarding molecular features and prognostic indicators.
DATA SOURCES.—
Peer-reviewed literature and archived cases for illustration.
CONCLUSIONS.—
Accurate histologic classification is essential, as PAM/C-MIN/CMILs that have a significant potential to progress to invasive melanoma may be clinically indistinguishable from low-risk lesions. Conjunctival melanoma (CM) more closely resembles cutaneous melanoma in terms of its pathogenesis and molecular features, compared to melanoma arising at other mucosal sites or to uveal melanoma. Depth of invasion and ulceration status, among other factors, have emerged as important prognostic indicators in CM. Sentinel lymph node biopsy may provide further prognostic information. Lastly, integration of pathologic and clinical findings is essential at this anatomically sensitive location to determine appropriate clinical management.
Topics: Conjunctival Neoplasms; Humans; Hyperpigmentation; Hyperplasia; Melanoma; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 34424954
DOI: 10.5858/arpa.2021-0006-RA