Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1. In contrast, LKB1 siRNA increased the expression of these target genes. The same results were shown to inhibit the Hh factors Sufu and Hip. Furthermore, we also observed negative correlation between LKB1 and glioma-associated oncogene homologue 1 (GLI1) in three breast cancer cell lines. Meanwhile, LKB1 siRNA rescued the inhibition of cell growth by 3-Keto-N-(aminoethyl-N'-aminocaproyldihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), an antagonist of the Hh element SMO, which suggests that LKB1 acts as the downstream of SMO. In vivo, LKB1 siRNA increased tumor growth in the mammary fat pad, and the expression levels of Hh displayed similar results in vitro. Overexpression of the LKB1 protein in human breast cancers is associated with the expression of Hh. We found that breast carcinomas with detectable Hh had weak or undetectable expression of LKB1, whereas tumors that expressed high levels of LKB1 had undetectable Hh signaling. In this study, we find that LKB1 are negatively correlated with the expression of Hh related transcription factors. These findings suggest that LKB1 may inhibit tumorigenesis by regulating Hh signaling in certain cancers.

Background /ObjectiveWe developed a Brain Computer Interface(BCI) robot system for movement recovery of upper limb motor function in post-stroke patients with severe hemiplegia. We designed and performed a randomized controlled clinical trial (RCT) to explore our hypothesis that motor functional recovery using this BCI robot system could be improved in a greater level in severe hemiparesis compared to that of hand robot rehabilitation. And we also focus on the neuroplastic changes between the primary motor cortices(M1) and frontal cortices before and after BCI intervention.Methods We will conduct a single blind, parallel-group trial and recruit subacute or chronic poststroke patients with severe hemiparesis more than 90 days after onset (N=50). Participants are randomly allocated to 2 intervention groups(1:1)by a computer-generated assignment: the BCI-assisted hand robot training(the BCI group,BG,n=25) and a hand robot training not supported by BCI(the robot group,RG, n=25).Both interventions will be delivered 5 sessions per-week for totally 4 weeks as add-on therapies to conventional rehabilitation. Motor functions of the paretic hands will be measured at 4 points: pre- (baseline), mid-(after 10 sessions), post-(after 20 sessions) and one month follow-up(4 weeks after the intervention).All investigators assessing outcomes will be masked to treatment assignment. Improvement in Wolf Motor Function Test (WMFT) will be used as the primary outcome,while Fugl-Meyer Assessment (FMA), its wrist and hand（FMA-WH）sub-score and its shoulder and elbow (FMA-SE) sub-score will be served as secondary outcome measures. Neuroplastic changes will be measured by functional near-infrared spectroscopy (fNIRS) at baseline and one-month follow up after 20 sessions BCI training. Pearson correlation analysis is used to evaluate functional connectivity(FC) across time points.Discussion We expect the BCI-based rewarding of hand robot practice to promote the motor recovery in upper limb motor outcome and also, this clinical improvement to be sustained by a long-lasting neuroplasticity changes promote by the BCI-based intervention.Recruitment started in June 2021. This trial is currently in the data correcting phase. This RCT is expected to be completed by June 30, 2023.Trial registration: Name of registry: Study on the Mechanism of Hand Motor Function Rehabilitation after Stroke. Trial registration number: ChiCTR2100046301; registration date on www.chictr.org.cn: May, 12/2021.

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