PHLDA2 reshapes the immune microenvironment and induces drug resistance in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a malignancy known for its unfavorable prognosis.The dysregulation of the tumor microenvironment(TME)can affect the sensitivity to immunotherapy or chemotherapy,leading to treatment failure.The elucidation of PHLDA2’s involvement in HCC is imperative,and the clinical value of PHLDA2 is also underestimated.Here,bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of HCC.Then,the expression and function of PHLDA2 were examined via the qRT-PCR,Western Blot,and MTT assays.Our findings indicate a substantial upregulation of PHLDA2 in HCC,correlated with a poorer prognosis.The methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver tissues.Besides,noteworthy associations were observed between PHLDA2 expression and immune infiltration in HCC.In addition,PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in HCC.In vitro experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels,and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy drugs.Meanwhile,we found that TGF-βinduced the expression of PHLDA2 in vitro.The GSEA and in vitro experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling pathway.Our study revealed the novel role of PHLDA2 as an independent prognostic factor,which plays an essential role in TME remodeling and treatment resistance in HCC.

Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression

More than 90% of hepatocellular carcinoma(HCC)cases develop in the presence of fibrosis or cirrhosis,making the tumor microenvironment(TME)of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts(CAFs)and cancer stem cells(CSCs),which collectively regulate HCC progression.However,the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive.Our study unveils a significant upregulation of Sema3C in fibrotic liver,HCC tissues,peripheral blood of HCC patients,as well as sorafenib-resistant tissues and cells,with its overexpression correlating with the acquisition of stemness properties in HCC.We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C,activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation.Additionally,HCCcells-derived Sema3Cfacilitated extracellular matrix(ECM)contraction and collagen deposition in vivo,while also promoting the proliferation and activation of hepatic stellate cells(HSCs).Mechanistically,Sema3C interacted with NRP1 and ITGB1 in HSCs,activating downstream NF-kB signaling,thereby stimulating the release of IL-6 and upregulating HMGCR expression,consequently enhancing cholesterol synthesis in HSCs.Furthermore,CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells,establishing a positive feedback loop that accelerates HCC progression.Notably,blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo.In sum,our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CsCs and stroma during hepatocarcinogenesis,thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.