Mucosal melanoma is a rare and highly malignant type of melanoma. Among the sites that mucosal melanoma arises, anorectal and gynecological melanoma has more aggressive behavior and worse prognosis. There was no effective therapy for mucosal melanoma at present. Only a small number of mucosal melanoma patients which harbor mutations in BRAF or KIT benefit from targeted therapy. So it’s an urgent need to identify more actionable mutations in mucosal melanoma. To identify more potential therapeutic targets in mucosal melanoma, 48 samples were collected from 44 patients with anorectal or gynecological melanoma and subjected to whole-exome sequencing. The tumor mutation burden was low with a median of 1.75 mutations per Mb. In chromosomal level, 1q, 6p and 8q of mucosal melanoma were significantly amplified while 9p, 10p, 10q, 16p and 16q were significantly deleted. Muc16 was the most frequently mutated oncogene in our samples(25%). The mutation frequency of KIT(20%) was comparable to the "triple-wild" genes-NRAS(20%), NF1(20%), and BRAF(11%). KMT2D mutation was found in 18.18% patients, which is previously unidentified. MAPK signaling pathway and lysine degradation were the most frequently mutated pathways. Moreover, patients with TP53 mutations tend to have worse clinical outcome (median survival time 19 vs. 50 months, log-rank P = 0.006). 2000 ore mutated genes involved in MAPK signaling pathway were identified, which expand the patients potentially benefit from ample MAPK inhibitors. KMT2D could be a potential therapeutic target. Moreover, TP53 could be a potential prognosis marker for mucosal melanoma.

CircRNAs, a type of non-coding RNA widely present in eukaryotic cells, have emerged as a prominent focus in tumor research. However, the functions of most circRNAs remain largely unexplored. Known circRNAs exert their regulatory roles through various mechanisms, including acting as microRNA sponges, binding to RNA-binding proteins, and functioning as transcription factors to modulate protein translation and coding. Tumor growth is not solely driven by gene mutations but also influenced by diverse constituent cells and growth factors within the tumor microenvironment (TME). As crucial regulators within the TME, circRNAs are involved in governing tumor growth and metastasis. This review highlights the role of circRNAs in regulating angiogenesis, matrix remodeling, and immunosuppression within the TME. Additionally, we discuss current research on hypoxia-induced circRNAs production and commensal microorganisms’ impact on the TME to elucidate how circRNAs influence tumor growth while emphasizing the significance of modulating the TME.

Osteosarcoma is a malignant bone tumor that is prone to metastasize early and primarily affects children and adolescents. Cell migration-inducing protein (CEMIP) plays a crucial role in the progression and malignancy of various tumor diseases, including osteosarcoma. Chitosan oligosaccharide (COS), an oligomer isolated from chitin, has been found to have significant anti-tumor activity in various cancers. This study investigates the effects of COS on CEMIP expression in osteosarcoma and explores the underlying mechanism. In present study, in vitro experiments were conducted to confirm the inhibitory activity of COS on human osteosarcoma cells. Our results demonstrate that COS possesses inhibitory effects against human osteosarcoma cells and significantly suppresses CEMIP expression in vitro. Next, we studied the inhibition of the expression of CEMIP by COS and then performed bioinformatics analysis to explore the potential inhibitory mechanism of COS against signaling pathways involved in regulating CEMIP expression. Bioinformatics analysis predicted a close association between the PI3K signaling pathway and CEMIP expression and that the inhibitory effect of COS on CEMIP expression may be related to PI3K signaling pathway regulation. The results of this study show that COS treatment significantly inhibits CEMIP expression and the PI3K/AKT/mTOR signaling pathway, as observed both in vitro and in vivo. This study demonstrates that COS could inhibit the expression of CEMIP, which is closely related to osteosarcoma malignancy. This inhibitory effect may be attributed to the inhibition of the PI3K/AKT/mTOR signaling pathway in vitro and in vivo.

The aim is to support the perception of artificial intelligence in the radiation therapy landscape.

Immunosuppressive cells play important roles in generating an immunosuppressive tumor microenvironment and facilitating tumor immune escape. However, the molecular mechanisms underlying their immunosuppressive effects remain unclear. UBA3, the sole catalytic subunit of the neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme E1, is highly expressed in various human malignancies, along with an activated neddylation pathway. In this study, we investigated the relationships between the UBA3-dependent neddylation pathway and the infiltration of several immunosuppressive cell populations in lung adenocarcinoma (LUAD). We explored the regulatory mechanisms of UBA3 in LUAD cells by using mRNA sequencing and functional enrichment analyses. Correlations between neddylation and immune infiltrates were assessed by Western blotting, real-time PCR, and analyses of public databases. We found elevated levels of UBA3 expression in LUAD tissues compared to adjacent normal tissues. Blocking UBA3 and the neddylation pathway promoted the accumulation of the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκBα), inhibiting the gene expression of tumor cell-derived cytokines such as C–C motif chemokine ligand (CCL) 2, C-X-C motif ligand (CXCL)1, CXCL2, colony-stimulating factor (CSF) 1, CSF2 interleukin (IL)-6, and IL-1B. Moreover, the overexpression of UBA3 in LUAD cells was associated with the secretion of these cytokines, and the recruitment and infiltration of immunosuppressive cells including tumor-associated macrophages (TAMs), plasmacytoid dendritic cells (pDCs), Th2 cells and T-regulatory cells (Tregs). This could facilitate the tumor immune escape and malignant progression of LUAD. Our findings provide new insights into the role of UBA3 in establishing an immunosuppressive tumor microenvironment by modulating nuclear factor kappa B (NF-кB) signaling and the neddylation pathway.

The prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant prostate cancer TME cells are macrophages, which can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages). A function of M2-like macrophages is efferocytosis, the phagocytosis of apoptotic cells. Based on literature from other models and contexts, efferocytosis further supports the M2-like macrophage phenotype. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. We hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages and that targeting MerTK-mediated efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate. The aims of this study are to measure efferocytosis of prostate cancer cells by in vitro human M1/M2 macrophage models and assess changes in the M2-like, pro-tumor macrophage phenotype following prostate cancer efferocytosis. Additionally, this study aims to demonstrate that targeting MerTK decreases prostate cancer efferocytosis and promotes an anti-tumor immune infiltrate. We have developed methodology using flow cytometry to quantify efferocytosis of human prostate cancer cells using the LNCaP cell line. We observed that M2 macrophages efferocytose the LNCaP cell line more than M1 macrophages. Following efferocytosis of LNCaP cells by M2 human monocyte-derived macrophages (HMDMs), we observed an increase in the M2-like, pro-tumor phenotype by flow cytometry cell surface marker analysis. By qRT-PCR, flow cytometry, and Western blot, we detected greater MerTK expression in M2 than M1 macrophages. Targeting MerTK with antibody Mer590 decreased LNCaP efferocytosis by M2 HMDMs, establishing the role of MerTK in prostate cancer efferocytosis. In the prostate cancer mouse model hi-myc, Mertk KO increased anti-tumor immune infiltrate including CD8 T cells. These findings support targeting MerTK-mediated efferocytosis as a novel therapy for prostate cancer.

Metformin is a regularly prescribed and low-cost generic medication. Metformin has been proposed as a target for Dipeptidyl-peptidase 4 (DPP4) expression in various clinical disorders. We provide insilco investigations on molecular docking and dynamic modeling of metformin and DPP4 potential interactions. Moreover, we conducted bioinformatic studies to highlight the clinical significance of DPP4 expression and mutation in various types of malignancies, as well as the invasion of different immune cells into the tumor microenvironment. We believe the present proposal’s findings have crucial implications for understanding how metformin may confer health advantages by targeting DPP4 expression in malignancies.Graphical abstract