Annexin A2 overexpression associates with colorectal cancer invasiveness and TGF-ß induced epithelial mesenchymal transition via Src/ANXA2/STAT3

Abstract

Annexin A2 (ANXA2) is upregulated in several malignancies, including colorectal cancer (CRC). However, there is little knowledge on the molecular mechanisms involved to its upregulation. The aim of this study was to identify the mechanism through which ANXA2 overexpression leads to CRC progression and evaluate its potential prognostic value. We used human CRC samples to analyse the correlation between ANXA2 levels and tumour staging. ANXA2 expression was increased in CRC tissues compared to normal colon tissues. In addition, we observe increased ANXA2 levels in stage IV tumours and metastasis, when compared to stage I-III. Whereas E-cadherin, an epithelial marker, decreased in stage II-IV and increased in metastasis. We’ve also shown that TGF-β, a classic EMT inductor, caused upregulation of ANXA2, and internalization of both E-cadherin and ANXA2 in CRC cells. ANXA2 silencing hindered TGF-β-induced invasiveness, and inhibitors of the Src/ANXA2/STAT3 pathway reversed the EMT. In silico analysis confirmed overexpression of ANXA2 and association to the consensus moleculars subtypes (CMS) with the worst prognosis. Therefore, ANXA2 overexpression play a pivotal role in CRC invasiveness through Src/ANXA2/STAT3 pathway activation. The association of ANXA2 to distinct CMSs suggests the possible use of ANXA2 as a prognostic marker or directed target therapy.

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

“…We have reported that pY23-Anxa2 binds to and enhances STAT3 activation and promotes invasion and metastasis of breast cancer cells [56]. Consistently, Anxa2 associates with STAT3 and confers the aggressive behavior in colorectal cancer [46,66]. Interestingly, Rack1 is also involved in the activation of STAT3 in several cancer cells [36,67].…”

“…A high level of Anxa2 in cancer tissues is correlated with a highly aggressive phenotype [15,46,[48][49][50][51]. Increased Anxa2 expression has been shown to be specific in many drug-resistant cancer cells [2,[16][17][18][19][20].…”

“…Src is a well-known upstream kinase of Anxa2 [45][46][47]. Therefore, to investigate whether the decreased level of pY23-Anxa2 is associated with the declined cell invasion ability in drug-resistant cells, we blocked Src kinase activity in drug-resistant cells by using Src kinase inhibitor KX2-391.…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…AnxA1 induces invasiveness, drug-resistance, and generation of CSCs in prostate and pancreatic cancer by increasing the p-STAT3 level [114]. In addition, EGF/EGFR and TGF-β induce AnxA2 activation, following which p-AnxA2 directly interacts with STAT3 and subsequently enhances EMT in BC and CRC [115,116].…”

A novel role for Myosin-Va in mitochondrial fission

“…Thin (0·1 mm) Z-stacks of high-resolution image frames were collected in 5 rotations by utilizing an alpha Plan-Apochromat 63×/1·46 oil DIC M27ELYRA objective. Image acquisition, reconstruction, and alignment for structured illumination microscopy were performed using the Zeiss ZEN 2012 SP1 software (black edition, version 8.1.5.484), as previously described 62 .…”