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Ovarian cancer (OC) is a particularly lethal disease due to intratumoral heterogeneity, resistance to traditional chemotherapy, and poor response to targeted therapy and immunotherapy. Interferon-γ (IFN-γ) is an attractive therapeutic cytokine, with positive responses achieved in multiple OC clinical trials. However, clinical application of IFN-γ in OC is still hindered, due to the severe toxicity when used at higher levels, as well as the considerable pro-metastatic adverse effect when used at lower levels. Thus, an effective combined intervention is needed to enhance the anti-tumor efficacy of IFN-γ and to suppress the IFN-γ-induced metastasis. Here, we uncovered that OC cells develop an adaptive strategy by upregulating midkine (MDK) to counteract the IFN-γ-induced anti-tumor activity and to fuel IFN-γ-induced metastasis. We showed that MDK is a critical downstream target of IFN-γ in OC, and that this regulation acts in a dose-dependent manner and is mediated by STAT1. Gain-of-function studies showed that MDK overexpression promotes cell proliferation and metastasis in OC, indicating that IFN-γ-activated MDK may antagonize IFN-γ in inhibiting OC proliferation but synergize IFN-γ in promoting OC metastasis. Subsequently, we assessed the influence of MDK inhibition on IFN-γ-induced anti-proliferation and pro-metastasis effects using an MDK inhibitor (iMDK), and we found that MDK inhibition robustly enhanced IFN-γ-induced growth inhibition (all CIs < 0.1) and reversed IFN-γ-driven epithelial-to-mesenchymal transition (EMT) and metastasis in OC in vitro. Collectively, these data identify an IFN-γ responsive protein, MDK, in counteracting anti-proliferation while endowing the pro-metastatic role of IFN-γ in cancer treatment, and we therefore propose the combined utilization of the MDK inhibitor in IFN-γ-based therapies in future OC treatment. [ABSTRACT FROM AUTHOR]

Cosmc is known as a T‐synthase‐specific molecular chaperone that plays a crucial role in the process of O‐glycosylation. Cosmc dysfunction leads to inactive T‐synthase and results in aberrant O‐glycosylation, which is associated with various tumour malignancies. However, it is unclear whether Cosmc has some other functions beyond its involvement in O‐glycosylation. In this study, we aimed to investigate the functional role of Cosmc in human colorectal cancer (CRC). We first assessed the expression levels of Cosmc in human CRC specimens and then forcedly expressed Cosmc in human CRC cell lines (HCT116, SW480) to examine its impact on cellular behaviours. The mechanisms for aberrant expression of Cosmc in CRC tissues and the altered behaviours of tumour cells were explored. It showed that the mRNA and protein levels of Cosmc were markedly elevated in human CRC specimens relative to normal colorectal tissues. The occurrence of endoplasmic reticulum (ER) stress may largely contribute to the increased Cosmc expression in cancer tissue and cells. Cosmc overexpression in CRC cells significantly promoted cell migration and invasion, which could be attributed to the activation of the epithelial‐mesenchymal transition (EMT) pathway rather than aberrant O‐glycosylation. These data indicate that Cosmc expression was elevated in human CRC possibly caused by ER stress, which further enhanced malignancies through the activation of EMT but independently of aberrant O‐glycosylation. [ABSTRACT FROM AUTHOR]

Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-β pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-β signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8 + T cell killing and lowered IFNAR1 expression in CD8 + T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8 + T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-β/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC., Competing Interests: LY, XD, ZL, JT, XH, TW, HQ, ZW No competing interests declared, (© 2022, Yang et al.)