Targeting CD43 optimizes cancer immunotherapy through reinvigorating antitumor immune response in colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is one of the most common malignancies worldwide, with dramatically increasing incidence and mortality for decades. However, current therapeutic strategies for CRC, including chemotherapies and immunotherapies, have only demonstrated limited efficacy. Here, we report a novel immune molecule, CD43, that can regulate the tumor immune microenvironment (TIME) and serves as a promising target for CRC immunotherapy. METHODS: The correlation of CD43 expression with CRC patient prognosis was revealed by public data analysis. CD43 knockout (KO) CRC cell lines were generated by CRISPR-Cas9 technology, and a syngenetic murine CRC model was established to investigate the in vivo function of CD43. The TIME was analyzed via immunohistochemical staining, flow cytometry and RNA-seq. Immune functions were investigated by depletion of immune subsets in vivo and T-cell functional assays in vitro, including T-cell priming, cytotoxicity, and chemotaxis experiments. RESULTS: In this study, we found that high expression of CD43 was correlated with poor survival of CRC patients and the limited infiltration of CD8+ T cells in human CRC tissues. Importantly, CD43 expressed on tumor cells, rather than host cells, promoted tumor progression in a syngeneic tumor model. Loss of CD43 facilitated the infiltration of immune cells and immunological memory in the TIME of CRC tumors. Mechanistically, the protumor effect of CD43 depends on T cells, thereby attenuating T-cell-mediated cytotoxicity and cDC1-mediated antigen-specific T-cell activation. Moreover, targeting CD43 synergistically improved PD-L1 blockade immunotherapy for CRC. CONCLUSION: Our findings revealed that targeting tumor-intrinsic CD43 could activate the antitumor immune response and provide particular value for optimized cancer immunotherapy by regulating the TIME in CRC patients.

Caffeic acid dimethyl ether alleviates alcohol-induced hepatic steatosis via microRNA-378b-mediated CaMKK2-AMPK pathway.

Alcoholic liver disease (ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Caffeic Acid Dimethyl Ether (CADE) significantly inhibits alcohol-induced hepatic steatosis in vivo through AMP-activated protein kinase (AMPK) pathway, but its in-depth mechanism remains unclear. This work aimed to clarify further mechanism of CADE in improving hepatic lipid accumulation in ALD through the microRNA-378b (miR-378b)-mediated Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-AMPK signaling pathway. Here, we reported that the hepatic or serum triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels were sharply escalated by ethanol while prominently decreased by CADE. Ethanol sharply up-regulated miR-378b expression while CADE effectively prevented the elevation of miR-378b in vivo. And treatment of CADE surely increased mRNA and protein expression of CaMKK2 as a kinase of AMPK and reduced lipid accumulation in the livers of alcohol-fed C57BL/6 mice. MiR-378b escalation exacerbated hepatic steatosis and inhibited CaMKK2-AMPK signaling, while miR-378b deficiency alleviated lipid accumulation and activated the CaMKK2 cascade. Furthermore, CADE alleviated the lipid deposition and reversed the disorder of CaMKK2-AMPK signaling pathway induced by miR-378b over-expression. However, knockdown of miR-378b eliminated the beneficial effect of CADE on lipid metabolism. In brief, our results showed that CADE ultimately improved hepatic lipid deposition by regulating the CaMKK2-AMPK signaling pathway through miR-378b.

microRNA-378b regulates ethanol-induced hepatic steatosis by targeting CaMKK2 to mediate lipid metabolism.

Alcoholic liver disease (ALD) has seriously harmed the health of people worldwide, but its underlying mechanisms remain unclear. This study aims to clarify the biological function of microRNA-378b (miR-378b) in ethanol (EtOH)-induced hepatic lipid accumulation. Here, we report miR-378b is over-expressed in EtOH-induced cells and EtOH-fed mice and finally accelerates lipid accumulation. MiR-378b directly targets Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a kinase of AMP-activated protein kinase (AMPK), and mediates the protein level of CaMKK2. Over-expression of miR-378b exacerbated the lipid accumulation induced by EtOH and inhibited CaMKK2 and the AMPK cascade while inhibition of miR-378b ameliorated lipid metabolism dysfunction in vivo and in vitro. In brief, our results show that miR-378b plays an important role in the regulation of lipid metabolism by directly targeting CaMKK2.

Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

miR-378b Regulates Insulin Sensitivity by Targeting Insulin Receptor and p110α in Alcohol-Induced Hepatic Steatosis.

Insulin resistance has been implicated in alcoholic liver disease. A previous study has shown that microRNAs (miRNAs) play a major role in the production, secretion, and function of insulin. MiRNAs are capable of repressing multiple target genes that in turn negatively regulate various physiological and pathological activities. However, current information on the biological function of miRNAs in insulin resistance is limited. The goal of the present study was to elucidate the role of miR-378b in alcohol-induced hepatic insulin resistance and its underlying mechanism. This study has observed that miR-378b is up-regulated in National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcoholic mouse models as well as in ethanol-induced L-02 cells in vitro. Furthermore, miR-378b overexpression impaired the insulin signaling pathway, and inhibition of miR-378b improved insulin sensitivity in vivo and in vitro. A mechanistic study revealed that IR and p110α are direct targets of miR-378b. Together, these results suggest that miR-378b controls insulin sensitivity by targeting the insulin receptor (IR) as well as p110α and possibly play an inhibitory role in the development of insulin resistance, thereby providing insights into the development of novel diagnostic and treatment methods.