The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients. In addition, decreased TH indicated larger tumor size, much more numbers of tumor, higher level of AFP, and the presence of cirrhosis. TH effectively impairs the growth and metastasis of HCC cells, a process dependent on the phosphorylation of serine residues (S19/S40). TH directly binds to Smad2 and hinders the cascade activation of TGFβ/Smad signaling with the treatment of TGFβ1. In summary, our study uncovered the non-metabolic functions of TH in the development of HCC and proposes that TH might be a promising biomarker for diagnosis as well as an innovative target for metastatic HCC.

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to β-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the β-catenin destruction complex, decreasing the phosphorylation of β-catenin, and activating the Wnt/β-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/β-catenin signaling pathway, providing a potential novel therapeutic target.

Metastasis is a significant cause of high mortality in lung cancer. Lymph node (LN) metastasis is the most common metastatic pathway in non-small cell lung cancer and the most crucial factor affecting the prognosis of NSCLC. Nevertheless, the molecular mechanism underlying metastasis is unknown. We demonstrated that higher NADK expression suggests worsened survival prognosis, and NADK expression positively correlates with the lymph node metastasis rate and TNM and AJCC stages in NSCLC patients. Moreover, patients with LN metastasis show higher NADK expression than those without LN metastasis. NADK can promote NSCLC progression by enhancing the migration, invasion, lymph node metastasis and growth of NSCLC cells. Mechanistically, NADK inhibits the ubiquitination and degradation of BMPR1A by interacting with Smurf1, further activating the BMPs signalling pathway and promoting ID1 transcription. In conclusion, NADK may be a potential diagnostic indicator and a novel therapeutic target for metastatic NSCLC.

Breast cancer stem cells (BCSCs) are the main drivers of recurrence and metastasis. However, commonly used drugs rarely target BCSCs. Via screenings, we found that Salt-inducible kinase 2 (SIK2) participated in breast cancer (BC) stemness maintenance and zebrafish embryos development. SIK2 was upregulated in recurrence samples. Knockdown of SIK2 expression reduced the proportion of BCSCs and the tumor initiation of BC cells. Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and β-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/β-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/β-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs.

Abstract Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, β-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. Significance: The identification of NME7 as an activator of Wnt/β-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.

N6-methyladenosine (m(6)A) modification has been reported as a critical regulator of gene transcript expression. Although m(6)A modification plays important roles in tumor development, its role in therapeutic resistance remains unknown. In this study, we aimed to examine the expression level of m(6)A-modification related proteins and elucidate the effect of m(6)A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m(6)A modification, YTHDC2, a m(6)A reader, was found to be consistently highly expressed in radioresistant NPC cells. Knocking down of YTHDC2 expression in radioresistant NPC cells improved the therapeutic effect of radiotherapyin vitroandin vivo, whereas overexpression of YTHDC2 in radiosensitive NPC cells exerted an opposite effect. Bioinformatics and mechanistic studies revealed that YTHDC2 could physically bound to insulin-like growth factor 1 receptor (IGF1R) messenger RNA and promoted translation initiation of IGF1R mRNA, which in turn activated the IGF1R-AKT/S6 signaling pathway. Thus, the present study suggests that YTHDC2 promotes radiotherapy resistance of NPC cells by activating the IGF1R/ATK/S6 signaling axis and may serve as a potential therapeutic target in radiosensitization of NPC cells.