SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer

Abstract

Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

“…Strikingly, modulation of mutp53 levels revealed that mutp53 disrupts the association between Stat3 and its robust negative regulator the tyrosine phosphatase SHP2, thereby protecting pStat3 from dephosphorylation (Figures 6E-6G). PTPN11/SHP2 is a tumor suppressor in liver cancer and CRC (Bard-Chapeau et al, 2011; Huang et al, 2017), and, indeed, SHP2 depletion increased Stat3 phosphorylation in CRC cells (Figure 6E). Importantly, p53 R248Q expression destroyed pStat3-SHP2 complexes while increasing the amount of mutp53-pStat3 complexes (Figure 6F).…”

“…They constitutively deregulate Jak2/Stat3 signaling through physical interaction with pStat3 and competitive displacement of its phosphatase SHP2, a negative regulator of Stat3, within the malignant epithelial compartment to promote growth and invasion. SHP2 is known to inhibit CRC cell proliferation via Stat3 dephosphorylation in vitro , and high SHP2 levels in tumors correlate with longer patient survival (Huang et al, 2017). Stat3 is a well-characterized driver of colon cancer and other solid tumors (Yu et al, 2014), promoting cell-cycle progression, invasion, EMT (Rokavec et al, 2014), and survival of human CRC-initiating cells (Lin et al, 2011).…”

<p>P53 Mutant p53^N236S Regulates Cancer-Associated Fibroblasts Properties Through Stat3 Pathway</p>

“…SHP2 is known to inhibit Stat3 phosphorylation, and high SHP2 levels in tumors correlate with longer cancer patient survival. 30 The coordinated action of the Stat3 pathway may help to fine-tune p53S in CAFs activation.…”

Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling

“…Another study showed that SHP2 expression is also repressed in human esophageal squamous cell cancer (ESCC), and SHP2 knockdown results in increased ESCC cell proliferation in vitro and in vivo, which corresponded with a significant increase in phosphorylated STAT3 [ 98 ]. Moreover, Huang et al [ 99 ] demonstrated that SHP2 inhibition of colorectal cancer cell proliferation and migration corresponded with the negative regulation of STAT3 by SHP2; more importantly, low expression levels of SHP2 and high expression levels of phosphorylated STAT3 were associated with poor patient prognosis and vice versa. As mentioned above, SHP2 has been shown to cooperate with SHP1 and TC-PTP to dephosphorylate STAT3 in response to UV irradiation as part of an initial protective response against skin carcinogenesis [ 80 ].…”