LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging

Krsnik, Dajana; Marić, Tihana; Bulić-Jakuš, Floriana; Sinčić, Nino; Bojanac, Ana Katušić

doi:10.3390/ijms23137245

Cited by 8 publications

(3 citation statements)

References 167 publications

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“…The RNA-binding protein Lin28 is present as two homologs, Lin28A and Lin28B. Lin28A, first identified in 1997 in research on C. elegans, is commonly present in mammals ( 117 , 118 ), while Lin28B was first identified in hepatocellular carcinoma; therefore, both are involved in the development and cancer ( 119 , 120 ). LIN28 homologs are typically expressed in undifferentiated and pluripotent cells, and their expression is then reduced in response to development and differentiation.…”

Section: Stat3/nf-kb/c-myc and Pd-l1mentioning

confidence: 99%

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

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The development of techniques and immunotherapies are widely applied in cancer treatment such as checkpoint inhibitors, adoptive cell therapy, and cancer vaccines apart from radiation therapy, surgery, and chemotherapy give enduring anti-tumor effects. Minority people utilize single-agent immunotherapy, and most people adopt multiple-agent immunotherapy. The difficulties are resolved by including the biomarkers to choose the non-responders’ and responders’ potentials. The possibility of the potential complications and side effects are examined to improve cancer therapy effects. The Head and Neck Squamous Cell Carcinoma (HNSCC) is analyzed with the help of programmed cell death ligand 1 (PD-L1) and Insulin-like growth factor (IGF). But how IGF and PD-L1 upregulation depends on IL-6, EGFR, and LIN28/Let7-related mechanisms are poorly understood. Briefly, IL-6 stimulates gene expressions of IGF-1/2, and IL-6 cross-activates IGF-1R signaling, NF-κB, and STAT3. NF-κB, up-regulating PD-L1 expressions. IL-6/JAK1 primes PD-L1 for STT3-mediated PD-L1 glycosylation, stabilizes PD-L1 and trafficks it to the cell surface. Moreover, ΔNp63 is predominantly overexpressed over TAp63 in HNSCC, elevates circulating IGF-1 levels by repressing IGFBP3, and activates insulin receptor substrate 1 (IRS1).TP63 and SOX2 form a complex with CCAT1 to promote EGFR expression. EGFR activation through EGF binding extends STAT3 activation, and EGFR and its downstream signaling prolong PD-L1 mRNA half-life. PLC-γ1 binding to a cytoplasmic motif of elevated PD-L1 improves EGF-induced activation of inositol 1,4,5-tri-phosphate (IP3), and diacylglycerol (DAG) subsequently elevates RAC1-GTP. RAC1-GTP was convincingly demonstrated to induce the autocrine production and action of IL-6/IL-6R, forming a feedback loop for IGF and PD-L1 upregulation. Furthermore, the LIN28-Let7 axis mediates the NF-κB-IL-6-STAT3 amplification loop, activated LIN28-Let7 axis up-regulates RAS, AKT, IL-6, IGF-1/2, IGF-1R, Myc, and PD-L1, plays pivotal roles in IGF-1R activation and Myc, NF-κB, STAT3 concomitant activation. Therefore, based on a detailed mechanisms review, our article firstly reveals that IL-6, EGFR, and LIN28/Let7-related mechanisms mediate PD-L1 and IGF upregulation in HNSCC, which comprehensively influences immunity, inflammation, metabolism, and metastasis in the tumor microenvironment, and might be fundamental for overcoming therapy resistance.

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Section: Stat3/nf-kb/c-myc and Pd-l1mentioning

confidence: 99%

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

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“…Classical oncogenes Wnt and Myc are also amplified in NSGCT [8]. There is also increasing recent concern on the role which micro-RNA's such as the lin-28 family play in testicular oncogenesis [50]. Proprotein convertases are also implicated [51].…”

Section: Tgct Pathobiologymentioning

confidence: 99%

State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA

Reece

Hulse

2022

IJERPH

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Background. The cause of the worldwide doubling-tripling of testicular cancer rates (TCRs) in recent decades is unknown. Previous cohort studies associated cannabis use with TCR including dose–response relationships but the contribution of cannabis to TCRs at the population level is unknown. This relationship was tested by analyzing annual trends across US states and formally assessed causality. Four US datasets were linked at state level: age-adjusted TCRs from Centers for Disease Control Surveillance Epidemiology and End Results database; drug use data from annual National Survey of Drug Use and Health including 74.1% response rate; ethnicity and median household income data from the US Census Bureau; and cannabinoid concentration data from Drug Enforcement Agency reports. Data was processed in R in spatiotemporal and causal inference protocols. Results. Cannabis-use quintile scatterplot-time and boxplots closely paralleled those for TCRs. The highest cannabis-use quintile had a higher TCR than others (3.44 ± 0.05 vs. 2.91 ± 0.2, mean ± S.E.M., t = 10.68, p = 1.29 × 10−22). A dose–response relationship was seen between TCR and Δ9-tetrahydrocannabinol (THC), cannabinol, cannabigerol, and cannabichromene (6.75 × 10−9 < p < 1.83 × 10−142). In a multivariate inverse probability-weighted interactive regression including race and ethnic cannabis exposure (ECE), ECE was significantly related to TCR (β-estimate = 0.89 (95%C.I. 0.36, 2.67), p < 2.2 × 10−16). In an additive geospatiotemporal model controlling for other drugs, cannabis alone was significant (β-estimate = 0.19 (0.10, 0.28), p = 3.4 × 10−5). In a full geospatial model including drugs, income and ethnicity cannabinoid exposure was significant (cannabigerol: β-estimate = 1.39 (0.024, 2.53), p = 0.0017); a pattern repeated at two spatial and two temporal lags (cannabigerol: β-estimate = 0.71 (0.05, 1.37), p = 0.0.0350; THC: β-estimate = 23.60 (11.92, 35.29), p = 7.5 × 10–5). 40/41 e-Values > 1.25 ranged up to 1.4 × 1063 and 10 > 1000 fitting causal relationship criteria. Cannabis liberalization was associated with higher TCRs (ChiSqu. = 312.2, p = 2.64 × 10−11). Rates of TC in cannabis-legal states were elevated (3.36 ± 0.09 vs. 3.01 ± 0.03, t = 4.69, p = 4.86 × 10−5). Conclusions. Cannabis use is closely and causally associated with TCRs across both time and space and higher in States with liberal cannabis legislation. Strong dose–response effects were demonstrated for THC, cannabigerol, cannabinol, cannabichromene and cannabidiol. Cannabinoid genotoxicity replicates all major steps to testicular carcinogenesis including whole-genome doubling, chromosomal arm excision, generalized DNA demethylation and chromosomal translocations thereby accelerating the pathway to testicular carcinogenesis by several decades.

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“…Lin28 is an evolutionarily conserved RNA-binding protein and also a regulator of let-7 microRNA genesis ( Krsnik et al, 2022 ). In the adult Drosophila testis, Lin28 is exclusively expressed in niche cells, wherein it has been demonstrated to be required for the maintenance of the number of niche cells and niche architecture ( Sreejith et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Lin28 is Required for Single Niche Development in the Drosophila Male Gonad

Sreejith,

Kim

2023

Dev. Reprod.

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A stem cell niche provides an environment that governs stem cell maintenance and division. Thus, the development of a proper niche is of prime importance to stem cell behaviors. Mechanisms of niche development are beginning to be revealed in the Drosophila male gonad. Niche cells are initially dispersed throughout the gonad, then assemble at its apical tip through the anterior migration of posteriorly located niche cells. The molecular mechanisms of this migration and assembly are still poorly understood. Here we show evidence suggesting that Lin28, an RNA-binding protein and regulator of let7 genesis, might be an intrinsic factor for the anterior migration of niche cells. We found that a dispersed, ectopic niche, a phenotype observed with anterior migration defects, occurs in lin28 mutant gonads. This phenotype is rescued by expression of lin28 in the niche cells. These findings suggest that Lin28 might be required for the anterior migration of niche cells.

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LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging

Cited by 8 publications

References 167 publications

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA

Lin28 is Required for Single Niche Development in the Drosophila Male Gonad

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