Highlight of 2023: big impacts of microRNAs in T cells.

In 2023, several significant discoveries on the function of microRNAs in the immune system were reported. Here we discuss several notable papers that revealed important functions in T cells.

Curcumol Reduces Aerobic Glycolysis and Overcomes Chemoresistance by Inducing Cdh1-Mediated Skp2 Ubiquitination.

Colorectal cancer (CRC) is the third most common cancer worldwide. The main obstacle in treating advanced CRC is tumor recurrence and metastasis due to chemoresistance. S-phase kinase associated protein 2 (Skp2), an E3 ligase, is highly associated with tumor resistance and a poor prognosis. The results of immunoblotting, immunohistochemical staining, ubiquitination analysis, and co-immunoprecipitation (co-IP) assay revealed that the plant curcuma, curcumol, is a novel Skp2 inhibitor for CRC treatment. Curcumol inhibits aerobic glycolysis in CRC by inducing Skp2 degradation. Co-immunoprecipitation results showed that curcumol enhanced the interaction between cadherin-1 (Cdh1) and Skp2 and led to the ubiquitination and degradation of Skp2. Curcumol exhibited significant antitumor effects against CRC, such as increased intrinsic apoptosis and decreased tumorigenic properties, both in vivo and in vitro. Furthermore, curcumol overcame 5-fluorouracil (5-Fu) resistance in CRC and induced apoptosis in 5-Fu-resistant CRC cells. The present data revealed a novel antitumor mechanism of glycolytic regulation by curcumol, suggesting that curcumol may be a potential chemical candidate for treating 5-Fu-resistant CRC.

Dihydromyricetin suppresses tumor growth via downregulation of the EGFR/Akt/survivin signaling pathway.

Deregulation of epidermal growth factor receptor (EGFR) signaling is frequently observed in non-small cell lung cancer (NSCLC). The present study aimed to determine the impact of dihydromyricetin (DHM) on NSCLC, a natural compound extracted from Ampelopsis grossedentata with various pharmacological activities. Results of the present study demonstrated that DHM may act as a promising antitumor agent for NSCLC therapy, inhibiting the growth of cancer cells in vitro and in vivo. Mechanistically, results of the present study demonstrated that exposure to DHM downregulated the activity of wild-type (WT) and mutant EGFRs (mutations, exon 19 deletion, and L858R/T790M mutation). Moreover, western blot analysis indicated that DHM induced cell apoptosis via suppression of the antiapoptotic protein, survivin. Results of the present study further demonstrated that depletion or activation of EGFR/Akt signaling may regulate survivin expression though modulating ubiquitination. Collectively, these results suggested that DHM may act as a potential EGFR inhibitor, and may provide a novel choice of treatment strategy for patients with NSCLC.

The role of ubiquitination and deubiquitination in tumor invasion and metastasis.

Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination system components, E3 ubiquitin ligases and deubiquitinases have the most prominent roles in modulating tumor metastasis. This review will briefly summarize the observations and underlying mechanisms of multiple E3 ubiquitin ligases and deubiquitinases to regulate tumor metastasis. Further, we will discuss the relationship and importance between ubiquitination components and tumor progression.

Molecular imaging of tumor-associated macrophages in cancer immunotherapy.

Tumor-associated macrophages (TAMs), the most abundant inflammatory cell group in the tumor microenvironment, play an essential role in tumor immune regulation. The infiltration degree of TAMs in the tumor microenvironment is closely related to tumor growth and metastasis, and TAMs have become a promising target in tumor immunotherapy. Molecular imaging is a new interdisciplinary subject that combines medical imaging technology with molecular biology, nuclear medicine, radiation medicine, and computer science. The latest progress in molecular imaging allows the biological processes of cells to be visualized in vivo, which makes it possible to better understand the density and distribution of macrophages in the tumor microenvironment. This review mainly discusses the application of targeting TAM in tumor immunotherapy and the imaging characteristics and progress of targeting TAM molecular probes using various imaging techniques.

Expression of the miR-17~92a cluster of microRNAs by regulatory T cells controls blood glucose homeostasis.

Regulatory T cells (Tregs) are a specialized immune cell type that play important roles in regulating immune responses. However, those found in adipose tissue, particularly visceral adipose tissue (VAT), have also been shown to exert metabolic regulatory functions. This study investigated the requirement of the miR-17~92a cluster of microRNAs in VAT Tregs and the impact on blood glucose. This cluster of microRNAs is one that we previously showed to be important for the fitness of Tregs found in secondary lymphoid organs. It was found that male mice with Treg-specific miR-17~92a deficiency are resistant to impaired glucose tolerance induced by a high-fat diet. However, high-fat feeding still impaired glucose tolerance in female mice with Treg-specific miR-17~92a deficiency. There was an increase in KLRG1- naïve Tregs and a loss of KLRG1+ terminally differentiated Tregs in the VAT of Treg-specific miR-17~92a-deficient male mice but not in female mice. The protection of male mice from high-fat feeding was also associated with increased interleukin-10 and reduced interferonγ expression by conventional CD4+ T cells and reduced interleukin-2 expression by both CD4+ and CD8+ T cells in the VAT. Together this suggests that expression of miR-17~92a by VAT Tregs regulates the effector phenotype of conventional T cells and in turn the metabolic function of adipose tissue and blood glucose homeostasis.

Prevalence and genotype distribution of HPV infection among 214,715 women from Southern China, 2012-2018: baseline measures prior to mass HPV vaccination.

BACKGROUND: The epidemiology on the human papillomavirus (HPV) among females in Southern China is not well-established. Baseline data on the prevalence of HPV infection in China prior to mass prophylactic HPV vaccination would be useful. Thus, this study aims to determine the type-specific HPV prevalence and distribution among females from Southern China prior to mass HPV vaccination. METHODS: A retrospective cross-sectional study employing 214,715 women attending ChenZhou NO.1 People's Hospital for cervical screening during 2012-2018 was conducted prior to widespread HPV vaccination. HPV genotype was detected using nucleic acid molecular diversion hybridization tests. The overall prevalence, age-specific prevalence, type distribution, and annual trend were analyzed. RESULTS: The overall HPV prevalence was 18.71% (95% confidence interval [CI], 18.55-18.88%) among Southern China females. During 2012-2018, the prevalence of HPV infection showed a downward tendency, from 21.63% (95% CI, 21.07-22.20%) in 2012 to 18.75% (95% CI, 18.35-19.16%) in 2018. Age-specific HPV distribution displayed a peak at young women aged less than 21 years (33.11, 95% CI, 31.13-35.15%), 20.07% (95% CI, 19.70-20.44%) among women aged 21-30 years, 17.29% (95% CI, 17.01-17.57%) among women aged 31-40 years, 17.23% (95% CI, 16.95-17.51%) among women aged 41-50 years, 21.65% (95% CI, 21.11-22.20%) among women aged 51-60 years, and 25.95% (95% CI, 24.86-27.07%) among women aged over 60 years. Of the 21 subtypes identified, the top three prevalent high-risk HPV (HR-HPV) genotypes were HPV52 (5.12%; 95% CI, 21.11-22.20%), - 16 (2.96%; 95% CI, 2.89-3.03%), and - 58 (2.51%; 95% CI, 2.44-2.58%); the predominant low-risk HPV (LR-HPV) genotypes were HPV81 (1.86%; 95%CI, 1.80-1.92%) and - 6 (0.69%; 95% CI, 0.66-0.73%) respectively. Incidence of HR-HPV only, LR-HPV only and mixed LR- and HR-HPV were 15.17, 2.07 and 1.47% respectively. Besides, single HPV infection accounted for 77.30% of all positive cases in this study. CONCLUSIONS: This study highlights 1) a high prevalence of HPV infection among females with a decreasing tendency towards 2012-2018, especially for young women under the age of 21 prior to mass HPV vaccination; 2) HPV52, - 16 and - 58 were the predominant HPV genotypes, suggesting potential use of HPV vaccine covering these HPV genotypes in Southern China.

Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin.

The E3 ligase S-phase kinase-associated protein 2(Skp2) is overexpressed in human cancers and correlated with poor prognosis, but its contributions to tumorigenesis and chemoresistance in nasopharyngeal carcinoma (NPC) are not evident. Herein we show that Skp2 is highly expressed in NPC tumor tissues and cell lines. Knockdown of Skp2 suppresses tumor cell growth, colony formation, glycolysis, and in vivo tumor growth. Skp2 promotes Akt K63-mediated ubiquitination and activation, which is required for EGF-induced Akt mitochondrial localization. Importantly, K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization. Overexpression of Skp2 impaired the intrinsic apoptotic pathway and confers cisplatin resistance. Moreover, ectopic expression of Myr-Akt1 or phosphomimetic HK2-T473D rescued cisplatin-induced tumor suppression in Skp2 knockdown stable cells. Also, depletion of Akt ubiquitination enhances the antitumor efficacy of cisplatin in vitro and in vivo. Finally, we demonstrated that Skp2 is positively correlated with p-Akt and HK2 in NPC tumor tissues. This study highlights the clinical value of Skp2 targeting in NPC treatment.