PYGB facilitates cell proliferation and invasiveness in non-small cell lung cancer by activating the Wnt–β-catenin signaling pathway

Brain-type glycogen phosphorylase (PYGB) has been correlated with the progression of various human malignancies; however, its effects and regulatory mechanisms in non-small cell lung cancer (NSCLC) are still unclear. We used Western blotting, immunohistochemistry, and qRT-PCR to verify that the protein and mRNA expression levels of PYGB are up-regulated in both NSCLC cell lines and tissues. The expression of PYGB was positively related to TNM stage, positive lymph node metastasis, and poor prognosis in patients with NSCLC. Moreover, overexpression of PYGB promoted cell proliferation, migration, and invasiveness, but inhibited apoptosis, in vitro. Immunofluorescence assays showed that overexpression of PYGB promoted the nuclear import and accumulation of β-catenin. By comparison, silencing PYGB produced the opposite effects. Further, overexpression of PYGB resulted in activation of the Wnt signaling pathway, and transfection with Sh-PYGB produced the opposite effect, and these effects were abrogated by XAV-939 (a β-catenin inhibitor) or overexpression of β-catenin, respectively. Finally, knockdown of PYGB inhibited tumor growth in a mouse model of xenograft tumors. These findings highlight the role of PYGB in the progression of NSCLC, and reveal a link between PYGB and the Wnt–β-catenin signaling pathway, thus providing a new potential target for treatment of NSCLC.

Download Full-text

KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

Cell Death and Differentiation ◽

10.1038/s41418-020-00651-5 ◽

2020 ◽

Author(s):

Wenwen Du ◽

Jianjie Zhu ◽

Yuanyuan Zeng ◽

Ting Liu ◽

Yang Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Small Cell Lung

Abstract In addition to the role of programmed cell death ligand 1 (PD-L1) in facilitating tumour cells escape from immune surveillance, it is considered as a crucial effector in transducing intrinsic signals to promote tumour development. Our previous study has pointed out that PD-L1 promotes non-small cell lung cancer (NSCLC) cell proliferation, but the mechanism remains elusive. Here we first demonstrated that PD-L1 expression levels were positively correlated with p-MerTK levels in patient samples and NSCLC cell lines. In addition, PD-L1 knockdown led to the reduced phosphorylation level of MerTK in vitro. We next showed that PD-L1 regulated NSCLC cell proliferation via Gas6/MerTK signaling pathway in vitro and in vivo. To investigate the underlying mechanism, we unexpectedly found that PD-L1 translocated into the nucleus of cancer cells which was facilitated through the binding of Karyopherin β1 (KPNB1). Nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, regulated the synthesis of Gas6 mRNA and promoted Gas6 secretion to activate MerTK signaling pathway. Taken together, our results shed light on the novel role of nPD-L1 in NSCLC cell proliferation and reveal a new molecular mechanism underlying nPD-L1-mediated Gas6/MerTK signaling activation. All above findings provide the possible combinational implications for PD-L1 targeted immunotherapy in the clinic.

Download Full-text