Does paraspinal muscle morphometry predict functional status and re-operation after lumbar spinal surgery? A systematic review and meta-analysis.

OBJECTIVES: Whether paraspinal muscle degeneration is related to poor clinical outcomes after lumbar surgery is still indistinct, which limits its clinical application. This study aimed to evaluate the predictive value of paraspinal muscle morphology on functional status and re-operation after lumbar spinal surgery. METHODS: A review of the literature was conducted using a total of 6917 articles identified from a search of PubMed, EMBASE, and Web of Science databases through September 2022. A full-text review of 140 studies was conducted based on criteria including an objective assessment of preoperative paraspinal muscle morphology including multifidus (MF), erector spinae (ES), and psoas major (PS) in addition to measuring its relationship to clinical outcomes including Oswestry disability index (ODI), pain and revision surgery. Meta-analysis was performed when required metrics could be calculated in ≥ three studies, otherwise vote counting model was a good alternative to show the effect direction of evidence. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. RESULTS: A total of 10 studies were included in this review. Of them, five studies with required metrics were included in the meta-analysis. The meta-analysis suggested that higher preoperative fat infiltration (FI) of MF could predict higher postoperative ODI scores (SMD = 0.33, 95% CI 0.16-0.50, p = 0.0001). For postoperative pain, MF FI could also be an effective predictor for persistent low back pain after surgery (SMD = 0.17, 95% CI 0.02-0.31, p = 0.03). However, in the vote count model, limited evidence was presented for the prognostic effects of ES and PS on postoperative functional status and symptoms. In terms of revision surgery, there was conflicting evidence that FI of MF and ES could predict the incidence of revision surgery in the vote count model. CONCLUSION: The assessment of MF FI could be a viable method to stratify patients with lumbar surgery by the risk of severe functional disability and low back pain. KEY POINTS: • The fat infiltration of multifidus can predict postoperative functional status and low back pain after lumbar spinal surgery. • The preoperative evaluation of paraspinal muscle morphology is conducive for surgeons.

The expression of S100A8/S100A9 is inducible and regulated by the Hippo/YAP pathway in squamous cell carcinomas.

BACKGROUND: S100A8 and S100A9, two heterodimer-forming members of the S100 family, aberrantly express in a variety of cancer types. However, little is known about the mechanism that regulates S100A8/S100A9 co-expression in cancer cells. METHODS: The expression level of S100A8/S100A9 measured in three squamous cell carcinomas (SCC) cell lines and their corresponding xenografts, as well as in 257 SCC tissues. The correlation between S100A8/S100A9, Hippo pathway and F-actin cytoskeleton were evaluated using western blot, qPCR, ChIP and Immunofluorescence staining tests. IncuCyte ZOOM long time live cell image monitoring system, qPCR and Flow Cytometry measured the effects of S100A8/S100A9 and YAP on cell proliferation, cell differentiation and apoptosis. RESULTS: Here, we report that through activation of the Hippo pathway, suspension and dense culture significantly induce S100A8/S100A9 co-expression and co-localization in SCC cells. Furthermore, these expressional characteristics of S100A8/S100A9 also observed in the xenografts derived from the corresponding SCC cells. Importantly, Co-expression of S100A8/S100A9 detected in 257 SCC specimens derived from five types of SCC tissues. Activation of the Hippo pathway by overexpression of Lats1, knockdown of YAP, as well as disruption of F-actin indeed obviously results in S100A8/S100A9 co-expression in attached SCC cells. Conversely, inhibition of the Hippo pathway leads to S100A8/S100A9 co-expression in a manner opposite of cell suspension and dense. In addition, we found that TEAD1 is required for YAP-induced S100A8/S100A9-expressions. The functional studies provide evidence that knockdown of S100A8/S100A9 together significantly inhibit cell proliferation but promote squamous differentiation and apoptosis. CONCLUSIONS: Our findings demonstrate for the first time that the expression of S100A8/S100A9 is inducible by changes of cell shape and density through activation of the Hippo pathway in SCC cells. Induced S100A8/S100A9 promoted cell proliferation, inhibit cell differentiation and apoptosis.

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63.

In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by ΔNp63 in cancer cells. Stable overexpression of S100A7 activates the NFκB pathway and inhibits the expression of ΔNp63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFκB, counteracts the inhibitory effect of S100A7 on the expression of ΔNp63 and its target genes. Depletion of S100A7 significantly promotes ΔNp63 expression. These data indicate that S100A7 acts as a suppressor of ΔNp63. Mechanistic examination finds that ΔNp63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and ΔNp63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity. Mol Cancer Res; 15(12); 1752-63. ©2017 AACR.

S100A7 promotes lung adenocarcinoma to squamous carcinoma transdifferentiation, and its expression is differentially regulated by the Hippo-YAP pathway in lung cancer cells.

Our previous study revealed that S100A7 was selectively expressed in lung squamous cell carcinoma tissues but not in adenocarcinoma. Thus far, the functions of S100A7 in lung cancer have remained largely unknown. Here, we reveal that S100A7 overexpression facilitates the transdifferentiation from adenocarcinoma (ADC) to squamous carcinoma (SCC) in several lung cancer cells, which is confirmed by an increase in DNp63 expression and a decrease in thyroid transcription factor 1 (TTF1) and aspartic proteinase napsin (napsin A) expression. Further study finds that activation of the Hippo pathway induces S100A7 expression and further confirms that nuclear YAP acts as a repressor of S100A7 in H292 cells. Subsequently, we verify that TEAD1 is required for YAP transcriptional repression of S100A7. More importantly, we determine that S100A7 overexpression partially rescues lung ADC to SCC transdifferentiation inhibited by YAP overexpression in all tested cells, suggesting that S100A7 and YAP have the opposite effects on lung ADC to SCC conversion. Taken together, our study demonstrates for the first time that S100A7 not only functions as a facilitator of adenous-squamous carcinoma phenotypic transition in lung cancer cells but also that its expression is differentially regulated by the Hippo-YAP pathway.