Girdin (GIV) Expression as a Prognostic Marker of Recurrence in Mismatch Repair–Proficient Stage II Colon Cancer

Abstract

Purpose Prognostic markers that identify patients with stage II colon cancers (CC) who are at risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. Experimental Design Expression of full-length GIV was evaluated by immunohistochemistry (IHC) using a newly developed monoclonal antibody together with a mismatch repair (MMR)-specific antibody panel in three stage II CC patient cohorts, ie. a training (n=192), test (n=317), and validation (n=181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated. Results For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR:2.78, p=0.013; LVI: HR 2.54, p=0.025) and combined test and validation (pooled) cohorts (GIV, HR:1.85, p=0.019; LVI, HR:2.52, p=0.0004). A risk model based on GIV expression and LVI-status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts (Training: 52.3% versus 84.8%; HR:3.74, 95%CI: 1.50–9.32; Test: 85.9% versus 97.9%, HR:7.83, 95%CI:1.03–59.54; Validation: 59.4% versus 84.4%, HR:3.71, 95%CI: 1.24–11.12). Conclusions GIV expression status predicts recurrence risk in patients with T3 pMMR stage II CC. A risk model combining GIV expression and LVI-status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms.

Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

“…To do this, we developed a scoring system by which the expression levels were evaluated by both intensity scores and proportion scores (Figure E). Statistical analysis of 76 cases of skin cancer showed that the expression level of Girdin was upregulated in most cases of squamous cell carcinoma of the skin (Figure F, Table ), suggesting a role of Girdin in cancer progression, as already shown for other types of cancer including breast, colon, and brain tumors . We also found that Girdin expression level correlated well with the differentiation of the cancer (Table ) and the expression of β‐ and α‐catenins as well as E‐cadherin (Table ), suggesting that Girdin synergizes with its partner proteins in the progression of skin cancer.…”

“…We and others have previously shown that Girdin is expressed by multiple types of cancers, where its expression correlated with cancer progression . In this study, we showed a role of Girdin in the collective invasion of skin cancer cells, where it interacts with β‐catenin, a component of the E‐cadherin complex .…”

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

“…These conclusions are in keeping with prior observations that polarity defects precede the onset of tumorigenesis when the LKB1-AMPK pathway is inhibited (Hezel et al., 2008), fueling the speculation that polarity defects may be one of the major mechanisms for tumor initiation when the energy sensing pathway is dysregulated (Hezel and Bardeesy, 2008). Multiple studies on GIV have demonstrated its role as a bona fide metastasis-related protein across a variety of cancers, primarily via its ability to initiate and amplify tyrosine-based G protein signals (Aznar et al, 2016; Ghosh, 2016) and couple it to actin cytoskeletal remodeling at the leading edge of migrating cells predominantly via interactions mediated by its C terminus [reviewed in (Ghosh, 2015)]. This study is the first of its kind that reveals the protective role of GIV's N terminus.…”

“…It is noteworthy that although multiple retrospective clinical trials have generally concluded that prolonged use of Metformin reduces the incidence of cancer, others have reported conflicting results, and several prospective clinical trials are underway to identify which target populations may specifically benefit from this drug [reviewed in (Kourelis and Siegel, 2012; Pryor and Cabreiro, 2015)]. Given the widespread long-term use of metformin as a prescription drug and its potential utility both in chemoprevention as well as chemotherapy, further studies are warranted to investigate if the GIV-expression status in tumors [e.g., its expression as a spliced isoform lacking the C terminus (Ghosh et al, 2010) or mutants that prevent phosphorylation by AMPK (current work), or its overexpression as full length (Ghosh et al, 2016)] may help identify which patients may benefit from the tumor suppressive actions of the Metformin.…”

Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer

“…It has been shown to be a signal transducer that modulates multiple signaling pathways (6, 10–16). Recently, girdin was reported to serve as a useful prognosticator adjunct to traditional staging strategies in colon cancer, and its high expression predicts a worse outcome in esophageal squamous cell carcinoma (17–19). However, the clinical implication of girdin in breast cancer has been investigated in a few studies involving small cohorts of patients.…”