Heterogeneous nuclear ribonucleoprotein A2/B1 is a negative regulator of human breast cancer metastasis by maintaining the balance of multiple genes and pathways

Abstract

Background: Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is an important RNA-binding protein that affects the RNA processing, splicing, transport and stability of many genes. hnRNPA2/B1 is expressed during proliferation and metastasis of various cancer types and promotes such processes. However, the precise role and mechanism of hnRNPA2/B1 in breast cancer remain unclear. Methods: The association of hnRNPA2/B1 with breast cancer metastasis was assessed using tissue chips, mouse models and publicly available data. The role and mechanism of hnRNPA2/B1 in breast cancer metastasis were studied in cell lines and mouse models. Findings: In contrast to other cancer research findings, hnRNPA2/B1 expression was negatively correlated with breast cancer metastasis. hnRNPA2/B1 inhibited MDA-MB-231 triple-negative breast cancer (TNBC) cell metastasis in vitro and in vivo. hnRNPA2/B1 knockout activated ERK-MAPK/Twist and GR-beta/TCF4 pathways but inhibited STAT3 and WNT/TCF4 signalling pathways. Profilin 2 (PFN2) promoted breast cancer cell migration and invasion, whereas hnRNPA2/B1 bound directly to the UAGGG locus in the 3 0 -untranslated region of PFN2 mRNA and reduced the stability of PFN2 mRNA. Interpretation: Our data supported the role of hnRNPA2/B1 in tumour metastasis risk and survival prediction in patients with breast cancer. The inhibitory role of hnRNPA2/B1 in metastasis was a balance of downstream multiple genes and signalling pathways. PFN2 downregulation by hnRNPA2/B1 might partly explain the inhibitory mechanism of hnRNPA2/B1 in breast cancer metastasis. Therefore, hnRNPA2/B1 might be used as a new prognostic biomarker and valuable molecular target for breast cancer treatments.

Identification of therapeutic targets and prognostic biomarkers from the hnRNP family in invasive breast carcinoma

“…The significant association among the hnRNP family members and clinicopathological features and survival outcomes of patients with cancer has been confirmed, indicating that hnRNPs are novel and promising cancer therapeutic targets and predictive biomarkers for treatment response and prognostic evaluation [ 16 , 26 – 31 ]. In BRCA, the hnRNP family members, including HNRNPA2B1, HNRNPC, HNRNPH1, HNRNPK, HNRNPM, and PTBP1, function as oncogenes in BRCA progression [ 7 , 8 , 18 , 32 – 36 ]. Liu et al reported that HNRNPA2B1 is a negative regulator of BRCA metastasis [ 36 ].…”

“…In BRCA, the hnRNP family members, including HNRNPA2B1, HNRNPC, HNRNPH1, HNRNPK, HNRNPM, and PTBP1, function as oncogenes in BRCA progression [ 7 , 8 , 18 , 32 – 36 ]. Liu et al reported that HNRNPA2B1 is a negative regulator of BRCA metastasis [ 36 ]. Hu et al revealed that HNRNPA2B1 knockdown inhibits cell proliferation, induces apoptosis, and prolonges the S phase of the cell cycle in MCF-7 and MDA-MB-231 cells via the STAT3 and ERK1/2 signaling pathways [ 37 ].…”

Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression

“…In addition, activation of pDCs contributed to higher killing efficacy of effector lymphocyte in TME of breast cancer model, including FLT3L-induced pDCs [ 120 , 121 ]. In yet another study, simultaneous inhibition of STAT3 and Tcf4 signaling pathways was reported to suppress the breast cancer cells metastasis both in vitro and in vivo [ 122 ]. Despite insufficient evidence, FLT3L/STAT3 cascade directly conducted pDC and anti-tumor immunity via Tcf4 in breast cancer.…”

Emerging roles of N6-methyladenosine (m6A) modification in breast cancer

“…Epithelial–mesenchymal transition (EMT) accelerates the progress of tumor metastasis [ 85 ]. Liu et al [ 86 ] demonstrated that hnRNPA2B1 inhibits EMT and metastasis in breast cancer by directly binding to PFN2 mRNA and reducing its stability. Conversely, eIF3m promotes breast cancer cell migration and invasion by activating EMT [ 71 ].…”