Qiang Zhou

BACKGROUND: Although an abundance of evidence has indicated that tumor-associated macrophages (TAMs) are associated with a favorable prognosis in patients with colon cancer, it is still unknown how TAMs exert a protective effect. This study examined whether TAMs are involved in hepatic metastasis of colon cancer. MATERIALS AND METHODS: One hundred and sixty cases of pathologically-confirmed specimens were obtained from colon carcinoma patients with TNM stage IIIB and IV between January 1997 and July 2004 at the Cancer Center of Sun Yat-Sen University. The density of macrophages in the invasive front (CD68TFHotspot) was scored with an immunohistochemical assay. The relationship between the CD68TFHotspot and the clinicopathologic parameters, the potential of hepatic metastasis, and the 5-year survival rate were analyzed. RESULTS: TAMs were associated with the incidence of hepatic metastasis and the 5-year survival rate in patients with colon cancers. Both univariate and multivariate analyses revealed that the CD68TFHotspot was independently prognostic of survival. A higher 5-year survival rate among patients with stage IIIB after radical resection occurred in patients with a higher macrophage infiltration in the invasive front (81.0%) than in those with a lower macrophage infiltration (48.6%). Most importantly, the CD68TFHotspot was associated with both the potential of hepatic metastasis and the interval between colon resection and the occurrence of hepatic metastasis. CONCLUSION: This study showed evidence that TAMs infiltrated in the invasive front are associated with improvement in both hepatic metastasis and overall survival in colon cancer, implying that TAMs have protective potential in colon cancers and might serve as a novel therapeutic target.

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), but its clinical effects are still limited. In this study we identify Quiescin sulfhydryl oxidase 1 (QSOX1) acting as a cellular pro-oxidant, specifically in the context of sorafenib treatment of HCC. QSOX1 disrupts redox homoeostasis and sensitizes HCC cells to oxidative stress by inhibiting activation of the master antioxidant transcription factor NRF2. A negative correlation between QSOX1 and NRF2 expression was validated in tumor tissues from 151 HCC patients. Mechanistically, QSOX1 restrains EGF-induced EGFR activation by promoting ubiquitination-mediated degradation of EGFR and accelerating its intracellular endosomal trafficking, leading to suppression of NRF2 activity. Additionally, QSOX1 potentiates sorafenib-induced ferroptosis by suppressing NRF2 in vitro and in vivo. In conclusion, the data presented identify QSOX1 as a novel candidate target for sorafenib-based combination therapeutic strategies in HCC or other EGFR-dependent tumor types.

BACKGROUND: Tumor-associated macrophages (TAMs), which form a large part of the tumor microenvironment, are normally regulated by metabolic reprogramming. However, the potential mechanisms of the immune-metabolism interaction between hepatocellular carcinoma (HCC) cells and TAMs remain unclear. METHODS: The candidate long non-coding RNAs (lncRNAs) were screened by Smart-seq based scRNA-seq method and then validated by qPCR. Immunostaining analysis was done to examine the levels of markers for TAMs and glycolysis. Exosomes from primary TAMs of human HCC tissues were isolated by centrifugation, and their internalization with lncRNAs was confirmed by immunofluorescence. The underlying mechanism of TAMs-derived exosomal lncRNA to HCC was confirmed by luciferase reporter assay and RNA immunoprecipitation. Metabolism regulation was evaluated through glucose consumption, lactate productions and extracellular acidification rates (ECARs). Mouse xenograft models were used to elucidate the in vivo effect of candidate lncRNAs on tumor growth. RESULTS: TAMs augment the aerobic glycolysis in HCC cells and their proliferation by the extracellular exosome transmission of a myeloid-derived lncRNA, M2 macrophage polarization associated lncRNA (lncMMPA). Mechanistically, lncMMPA not only could polarize M2 macrophage, but also could act as an microRNA sponge to interact with miR-548 s and increase the mRNA level of ALDH1A3, then further promote glucose metabolism and cell proliferation in HCC. Moreover, lncMMPA increased HCC cell multiplication through interacting with miR-548 s in vivo. Clinically, lncMMPA expression associates with glycolysis in TAMs and reduced survival of HCC patients. CONCLUSION: LncMMPA plays an important role in regulating HCC malignancy and metabolic reprogramming of miR-548 s/ALDH1A3 pathway.

Within the immune system there is an exquisite ability to discriminate between "self" and "non-self" that is orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (Treg) or effector (Teff) T cells, influenced by cues from the naïve T cell's immediate micro-environment as it responds to cognate antigen. Reciprocal pathways may lead to commitment of naïve T cells into either the protective tolerance-promoting Treg, or to the pro-inflammatory Th17 effector phenotype. Primary activation of CD4(+) lymphocytes stimulates their release of leukemia inhibitory factor (LIF), and Treg continue to release LIF in response to antigen, implying a role for LIF in tolerance. In contrast, interleukin- 6 (IL-6), although very closely related to LIF, promotes maturation of Th17 cells. Here we show that LIF and IL-6 behave as polar opposites in promoting commitment to the Treg and Th17 lineages. Unlike IL6, LIF supported expression of Foxp3, the Treg lineage transcription factor, and LIF opposed IL6 by suppressing IL-6-induced IL-17A protein release. In striking contrast, we found that IL6 effectively inhibited LIF signalling, repressing transcription of the LIF receptor gp190, and strongly inducing axotrophin/MARCH-7, a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein. In vivo, anti-LIF treatment reduced donor-specific Treg in recipients of foreign spleen cells. Conversely, a single dose of biodegradable LIF nanoparticles, targeted to CD4, successfully manipulated the LIF/IL6 axis towards development of donor-specific Foxp3(+) Treg. The implications for therapy are profound, harnessing endogenous immune regulation by paracrine delivery of LIF to CD4(+) cells in vivo.