GALNT3 suppresses lung cancer by inhibiting myeloid-derived suppressor cell infiltration and angiogenesis in a TNFR and c-MET pathway-dependent manner.

The deregulation of polypeptide N-acetyl-galactosaminyltransferases (GALNTs) contributes to several cancers, but their roles in lung cancer remain unclear. In this study, we have identified a tumor-suppressing role of GALNT3 in lung cancer. We found that GALNT3 suppressed lung cancer development and progression in both xenograft and syngeneic mouse models. Specifically, GALNT3 suppressed lung cancer initiation by inhibiting the self-renewal of lung cancer cells. More importantly, GALNT3 attenuated lung cancer growth by preventing the creation of a favorable tumor microenvironment (TME), which was attributed to GALNT3's ability to inhibit myeloid-derived suppressor cell (MDSC) infiltration into tumor sites and subsequent angiogenesis. We also identified a GALNT3-regulated gene (GRG) signature and found that lung cancer patients whose tumors exhibit the GRG signature showed more favorable prognoses. Further investigation revealed that GALNT3 suppressed lung cancer cell self-renewal by reducing ß-catenin levels, which led to reduced expression of the downstream targets of the WNT pathway. In addition, GALNT3 inhibited MDSC infiltration into tumor sites by suppressing both the TNFR1-NFκB and cMET-pAKT pathways. Specifically, GALNT3 inhibited the nuclear localization of NFκB and the c-MET-induced phosphorylation of AKT. This then led to reduced production of CXCL1, a chemokine required for MDSC recruitment. Finally, we confirmed that the GALNT3-induced inhibition of the TNFR1-NFκB and cMET-pAKT pathways involved the O-GalNAcylation of the TNFR1 and cMET receptors. In summary, we have identified GALNT3 as the first GALNT member capable of suppressing lung cancer and uncovered a novel mechanism by which GALNT3 regulates the TME.

hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2.

Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3'UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.

GALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment.

Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self-renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage-derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms.