M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non-coding RNA taurine-upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3-mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1-like macrophages in tumors, promoted the activation of CD8+ T cells through PD-L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD-L1 and CD47 expressions by acting as a sponge of miR-141 and miR-340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD-L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD-L1 and CD47 in HCC tissues. Moreover, the combination of Tug1-siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.

Cordycepin enhances anti-tumor immunity in colon cancer by inhibiting phagocytosis immune checkpoint CD47 expression.

Cordycepin, also known as 3'-deoxyadenosine, is an extract from Cordyceps militaris, which has been reported as an anti-inflammation and anti-tumor substance without toxicity. However, the pharmacological mechanism of Cordycepin on tumor immunity under its anti-tumor effect has not yet been elucidated. Herein, we investigated Cordycepin's anti-tumor effect on colon cancer both in vitro and in vivo. Our results show that Cordycepin can inhibit growth, migration, and promoted apoptosis of CT26 cells in a dose-dependent manner. Cordycepin suppressed the growth of colon cancer in mouse subcutaneous tumor model by modulating tumor immune microenvironment where CD4+ T, CD8+ T, M1 type macrophages, NK cells were up-regulated. Further investigations revealed that Cordycepin inhibited phagocytosis immune checkpoint CD47 protein expression by reducing BNIP3 expression. In addition, Cordycepin also inhibited the expression of TSP1 in tumor cells and Jurkat cells, which may reduce the binding of TSP1 to CD47, thereby reducing T cell apoptosis and allowing more T cells to infiltrate into tumors. And in vitro co-culture experiments proved that Cordycepin could enhance the phagocytosis of CT26 cells by macrophages. These results explained the underlying mechanism of the anti-tumor immunity of Cordycepin. In conclusion, our results identify a novel mechanism by which Cordycepin inhibits phagocytosis immune checkpoint CD47 in tumor cells to promote tumor cells phagocytosis of macrophages. Cordycepin may be able to serve as a more effective immunotherapeutic drug against colon cancer.

Targeting TRIM54/Axin1/ß-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma.

Accumulating evidence demonstrates that dysregulation of ubiquitin-mediated degradation of oncogene or suppressors plays an important role in several diseases. However, the function and molecular mechanisms of ubiquitin ligases underlying hepatocellular carcinoma (HCC) remain elusive. In the current study, we show that overexpression of TRIM54 was associated with HCC progression. TRIM54 overexpression facilitates proliferation and lung metastasis; however, inhibition of TRIM54 significantly suppressed HCC progression both in vitro and in vivo. Mechanically, we demonstrated that TRIM54 directly interacts with Axis inhibition proteins 1 (Axin1) and induces E3 ligase-dependent proteasomal turnover of Axin1 and substantially induces sustained activation of wnt/ß-catenin in HCC cell lines. Furthermore, we showed that inhibition of the wnt/ß-catenin signaling pathway via small molecule inhibitors significantly suppressed TRIM54-induced proliferation. Our data suggest that TRIM54 might function as an oncogenic gene and targeting the TRIM54/Axin1/ß-catenin axis signaling may be a promising prognostic factor and a valuable therapeutic target for HCC.