RNA-Binding Protein La Mediates TGFβ-Induced Epithelial to Mesenchymal Transition and Cancer Stem Cell Properties

Abstract

Background: the aberrant overexpression of predominantly nuclear localizing RNA-binding protein (RBP) La contributes to proliferation, mobility, and chemoresistance of cancer cells and tumor growth in mice. Methods: studies included cancer tissue microarrays (TMAs) analyses, cancer tissue data mining, transforming growth factor β (TGFβ)-induced cancer cell plasticity studies, three dimensional sphere growth, epithelial to mesenchymal transition (EMT) assays, analysis of cancer stem cell (CSC) marker expression, and post-translational modification of cancer-associated La protein. Results: we demonstrated that significant overexpression of RBP La in lung and head and neck cancer tissue correlates with poor overall survival. Furthermore, small interfering RNA-mediated depletion of La reduced proliferation and migration of cancer cells, blocked TGFβ-induced EMT, and diminished both EMT and CSC marker expression. Rescue experiments with La wildtype but not RNA chaperone domain activity-defective La mutant increased the expression of those cancer progression markers, suggesting a critical role of La’s RNA chaperone activity in this process. La depletion in cancer cells also significantly decreased sphere growth in the presence of TGFβ. Interestingly, TGFβ treatment induced phosphorylation of La at threonine 389 (pLaT389) only in adherents but not in 3D growing cultures. Conclusion: our study suggests that the TGFβ/AKT/pLaT389 signaling pathway regulates cancer cell plasticity.

Upregulated SSB Is Involved in Hepatocellular Carcinoma Progression and Metastasis through the Epithelial-Mesenchymal Transition, Antiapoptosis, and Altered ROS Level Pathway

“…The cells change to a spindle-shaped mesenchymal morphology and express markers associated with the mesenchymal cell state, such as N-cadherin, Vimentin, and fibronectin [ 42 , 43 ]. Previous studies have shown that the gene SSB is associated with EMT, and the motility and invasion ability of squamous cell carcinoma cells are decreased after knockdown of SSB, and the expression of matrix metalloproteinase 2 (MMP-2) protein is significantly decreased [ 12 , 17 ].…”

“…The specific information is as follows: sh-scramble (5 ′ -TGTGAGGAA CTTGAGATCT-3 ′ ), sh-SSB1 (5 ′ -CCTGCATCCAAACA ACAGAAA-3 ′ ) and sh-SSB2 (5 ′ -GCTGAAATGAAATCTC TAGAA-3 ′ ). The shSSB base sequence is based on previously studied and verified sequence information [17].…”

Advancement in Cancer Stem Cell Biology and Precision Medicine—Review Article Head and Neck Cancer Stem Cell Plasticity and the Tumor Microenvironment

“…As such it is this small subset of cells that needs to be targeted in order to eradicate the tumor ( Bao et al, 2006 ; Dick 2008 ; Al-Assar et al, 2009 ; Mroz et al, 2013 ; Dionne et al, 2015 ; Subramanian et al, 2017 ; Zonga et al, 2018 ; Hu et al, 2019 ; Shibata and Hoque 2019 ; Keysar et al, 2020 ; Saito et al, 2021 ). More recently there has been an evolution in this model that suggests an inherent plasticity to CSCs that is mediated through the TME, arguing against the unidirectionality of the CSCs models ( Chaffer et al, 2013 ; Sancho et al, 2015 ; Shimokawa et al, 2017 ; Ahmed et al, 2018 ; Yao et al, 2019 ; Heise and Sommer 2021 ). This highlights the importance of a deeper understanding of the plasticity and interactions with the TME to identify new ways to target cancer stem cells to move the field forward.…”

La protein regulates protein expression by binding with the mRNAs of target genes and participates the pathological process of ovarian cancer

“…La protein is highly expressed in various malignant tumors, and its expression is related to the clinical TNM stage, lymph node metastasis, and differentiation degree of tumor cells, which plays an important role in the translation control of tumor promoters ( 10 – 13 ). It can promote the tumorigenicity, change the cell cycle, and promote the proliferation, migration, and invasion of cancer cells ( 12 , 14 , 15 ).…”

“…It can also promote the translation of Bcl-2, which may promote drug resistance by inhibiting the apoptosis of cancer cells. La protein mediates transforming growth factor β (TGF β)-induced epithelial–mesenchymal transition and cancer stem cell characteristics, contributing to the proliferation, migration, chemoresistance, and tumor growth of mouse cancer cells ( 10 ). It is an essential component of the X-linked inhibitor of apoptosis protein (XIAP) IRES ribonucleoprotein complex.…”