CMTR1 promotes colorectal cancer cell growth and immune evasion by transcriptionally regulating STAT3.

CMTR1, also called IFN-stimulated gene 95 kDa protein (ISG95), is elevated by viral infection in a variety of cells. However, the functions of CMTR1 in colorectal cancer (CRC), especially its roles in tumorigenesis and immune regulation, remain unclear. Here, we first identified CMTR1 as a novel oncogene in colorectal cancer. Based on The Cancer Genome Atlas (TCGA) database exploration and human tissue microarray (TMA) analysis, we found that CMTR1 expression was markedly higher in CRC tissues than in adjacent normal tissues. High CMTR1 expression was correlated with poor prognosis in CRC patients. Knockdown (KD) of CMTR1 significantly suppressed cell proliferation and tumorigenicity both in vitro and in vivo, whereas overexpression of CMTR1 resulted in the opposite effects. KEGG pathway analysis revealed differential enrichment in the JAK/STAT signaling pathway in colorectal cancer cells with CMTR1 KD. Mechanistically, suppression of CMTR1 expression inhibited RNAPII recruitment to the transcription start site (TSS) of STAT3 and suppressed STAT3 expression and activation. Furthermore, the efficacy of PD1 blockade immunotherapy was prominently enhanced in the presence of CMTR1 KD via increased infiltration of CD8 + T cells into the tumor microenvironment. Overall, it appears that CMTR1 plays a key role in regulating tumor cell proliferation and antitumor immunity.

A Tumor-suppressive Molecular Axis EP300/circRERE/miR-6837-3p/MAVS Activates Type I IFN Pathway and Antitumor Immunity to Suppress Colorectal Cancer.

PURPOSE: The oncogenic role of circular RNAs (circRNA) has been well studied in cancers including colorectal cancer. However, tumor-suppressive circRNAs and the mechanism through which they exert their antitumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets. EXPERIMENTAL DESIGN: circRNA sequencing, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to find tumor-suppressive and antitumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus (AAV) to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors. RESULTS: circRERE is lowly expressed in colorectal cancer. Overexpression of circRERE inhibits the malignant behaviors of colorectal cancer in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in colorectal cancer as well. Mechanistically, circRERE acts as a competitive endogenous RNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting antitumor immunity. Delivery of circRERE-AAV elicits significant antitumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of colorectal cancer. CONCLUSIONS: These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in antitumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic.

Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma.

Oxidative stress and hypoxia are two opposite microenvironments involved in HCC metastasis. Thioredoxin (TXN) and hypoxia-inducible factor 2α (HIF-2α) are typical proteins involved in these two different microenvironments, respectively. How these two factors interact to influence the fate on tumor cells remains unknown. Hypoxia facilitated HCC cells withstood oxidative stress and eventually promoted HCC cells metastasis, in which TXN and HIF-2α were mostly involved. Upregulation of TXN/HIF-2α correlated with poor HCC prognosis and promoted HCC metastasis both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) process was involved in TXN/HIF-2α-enhanced invasiveness of HCC cells. Additionally, the stability and activity of HIF-2α were precisely regulated by TXN via SUMOylation and acetylation, which contributed to HCC metastasis. Our data revealed that the redox protein TXN and HIF-2α are both associated with HCC metastasis, and the fine regulation of TXN on HIF-2α contributes essentially during the process of metastasis. Our study provides new insight into the interaction mechanism between hypoxia and oxidative stress and implies potential therapeutic benefits by targeting both TXN and HIF-2α in the treatment of HCC metastasis.

Correction to: miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a.

The original article [1] contains an error in Fig. 5a whereby the Western blot bands representing CyclinD1 have mistakenly been duplicated over the Western blot bands intended to represent SGK.

miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a.

BACKGROUND: High frequency of recurrence is the major cause of the poor outcomes for patients with hepatocellular carcinoma (HCC). microRNA (miR)-182-5p emerged as a high-priority miRNA in HCC and was found to be related to HCC metastasis. Whether the expression of miR-182-5p in tumor tissue correlated with early recurrence in HCC patients underwent curative surgery was unknown. METHODS: Real-time PCR (RT-PCR) and in situ hybridization (ISH) were conducted to assess the expression of miR-182-5p in HCC cells and tissues. Cell Counting Kit-8 (CCK-8), transwell assays were performed to detected cells proliferation and migration ability. Flow cytometry assays were used to detect cell apoptosis rate, and xenograft model was employed to study miR-182-5p in HCC growth and lung metastasis. The target of miR-182-5p was validated with a dual-luciferase reporter assay and western blotting. Immunohistochemistry, immumoblotting, and immunoprecipitation were performed to test relative protein expression. RESULTS: We showed that high expression of miR-182-5p in tumor tissues correlated with poor prognosis as well as early recurrence in HCC patients underwent curative surgery. miR-182-5p enhanced motility and invasive ability of HCC cells both in vitro and in vivo. miR-182-5p directly targets 3'-UTR of FOXO3a and repressed FOXO3a expression, activating AKT/FOXO3a pathway to promote HCC proliferation. Notably, miR-182-5p activated Wnt/ß-catenin signaling by inhibiting the degradation of ß-catenin and enhancing the interaction between ß-catenin and TCF4 which was mediated by repressed FOXO3a. CONCLUSIONS: Consistently, miR-182-5p can be a potential predictor of early recurrence for HCC patients underwent curative surgery, and FOXO3a plays a key mediator in miR-182-5p induced HCC progression.