NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway

Abstract

Background Salivary adenoid cystic carcinoma (SACC) can recur after removal of the primary tumor and treatment, where they can keep no clinical symptoms and dormant state for 10–15 years. NR2F1 has been demonstrated to regulate the tumor cell dormancy in various malignant tumors and has a potential impact on recurrence and metastasis of carcinoma. However, the role and significance of NR2F1 in SACC dormancy still remain unknown. Methods A total number of 59 patients with a diagnosis of SACC were included to detected expression of NR2F1, Ki-67 by immunohistochemical (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling (TUNEL). Fisher’s exact test was used to examine the NR2F1 expression and clinicopathologic parameters of SACC. In vitro, SACC cell lines were transfected NR2F1 and knockdown NR2F1 respectively. CCK-8, flow cytometry, wound healing assay and transwell invasion determined SACC cell proliferation, apoptosis, cell cycle, migration and invasion respectively. Chromatin immunoprecipitation (ChIP) assays were utilized to demonstrate the potential role of NR2F1 in SACC invasion via CXCL12/CXCR4 axis. In vivo, xenografts of nude mice via subcutaneous injection or tail vein injection were used to testify the results in vitro. Results Among the 59 patients with SACC, 23.73% (14/59) were positive to NR2F1 expression, a lower rate of expression compared with 60% (6/10) in normal salivary gland samples. NR2F1 was correlated with metastasis, relapse and dormancy of SACC. SACC cells with transfected NR2F1 remained dormant, as well as enhanced invasion and metastasis. Knockdown of NR2F1 via siRNA after NR2F1 overexpression restored the proliferation and the cell number in G2/M phases, and reduced the abilities of migration and invasion. In addition, NR2F1 promoted the expression of CXCL12 and CXCR4, and overexpression of CXCL12 at least partly rescued the proliferation, migration, and invasion activities induced by NR2F1 silencing. Conclusions NR2F1 may be an underlying mechanism of SACC recurrence and metastasis via regulating tumor cell dormancy through CXCL12/CXCR4 pathway.

Targeting dormant tumor cells to prevent cancer recurrence

“…Several studies have tried to define DCCs by biomarkers that associate to a dormant cell state, such as low levels of proliferation-associated protein Ki67 [14] in combination with lack of apoptotic markers such as TUNEL and M30 [7,15]. In addition, dormancy-regulating and -inducing signaling cascades have been identified, including members of the TGF-β family, reduced PI3K/AKT signaling, or p38 expression, which can serve as markers for DCCs [16,17].…”

“…To initiate a distant recurrence after treatment, these disseminated tumor cells therefore need to originate either from cells that escaped before local treatments by early dissemination, or from resistant cells that survived local or systemic treatment. Although disease relapse can occur shortly after treatment, many cases are described of metastatic disease occurring years or even decades after the first diagnosis and subsequent treatment, suggesting that cells initiating recurrence are often long-lived and able to reactivate proliferation after long latency periods (also referred to as clinical dormancy) [5][6][7]. Recurrent cancer has often acquired resistance mechanisms to the primary treatment, which in turn results in more aggressive tumor behavior and poor clinical outcome [8,9].…”

Inhibition of DEC2 is Necessary for Exiting Cell Dormancy in Salivary Adenoid Cystic Carcinoma 

“…Our previous ndings have demonstrated that atRA treatment can be used to induce dormancy in SACC cells, and its effects on cancer dormancy resulted directly from modulation of NR2F1 [15,16]. To further examine the molecular mechanism of tumor dormancy of SACC, atRA treated SACC-83 and the control cells were injected subcutaneously into nude mice, respectively.…”

“…drived tumor dormancy in HNSCC and breast cancer [13,31]. Our previous study has demonstrated that atRA treatment could also drive tumor dormancy of SACC by upregulating NR2F1 [15]. Sosa et al…”

Switching Homes: How Cancer Moves to Bone

“…However, Abravanel and colleagues obtained different results when investigating the Notch family [181], likely because fine-tuning such an important pathway might cause dramatic differences, as is shown in other reports in the literature [176]. Another pathway that is still under investigation in this regard is the already cited SDF-1/CXCR4 pathway, which might partake in this process as well, although there is currently no consensus on the matter, and results seem to be pointing at different directions in different cancers [182][183][184][185].…”