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Background: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73-counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

Training including exercise therapy, electrical stimulation, functional electrical stimulation of the upper limb following cervical spinal cord injury leads to improvements in muscle strength, upper limb function and activity of daily living or quality of life. Further research is needed into the effects of repetitive transcranial magnetic stimulation and robotic training on upper limb function.

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After a stroke, it is essential that recovery of function of the upper limb is maximized in order to enable activities of daily living. The hand plays an important role in the function of the upper limb. This study examined the effectiveness of contralaterally controlled functional electrical stimulation (CCFES) on recovery of active dorsiflexion of the wrist and upper limb functioning in patients in the early-phase after stroke (<15 days post-stroke). CCFES significantly shortened the time for regaining wrist dorsiflexion, and improved the upper extremity function and general health of patients with early-phase stroke, compared with conventional neuro muscular electrical stimulation. CCFES therefore has potential as a clinical intervention. Objectives: To investigate the effectiveness of contra laterally controlled functional electrical stimulation (CCFES) on the recovery of active wrist dorsiflexion and upper limb function in patients with early-phase stroke (<15 days poststroke). Methods: Patients in the CCFES group were treated with routine rehabilitation combined with CCFES, while those in the conventional neuromuscular electrical stimulation (NMES) group were treated with routine rehabilitation combined with NMES. Time intervals from stroke onset to appearance of wrist dorsiflexion, and from onset of treatment to appearance of wrist dorsiflexion were recorded (in days). Functional assessments were also performed at baseline and endpoint. Results: Nineteen out of 21 patients in the CCFES group and 12 out of 20 patients in the NMES group regained active wrist dorsiflexion during the treatment and follow-up period (90.5% vs 60%, p = 0.025). The mean time interval from onset of treatment to appearance of active wrist dorsiflexion was signifcantly shorter in the CCFES group than in the NMES group (p < 0.001). The CCFES group had signifcantly higher scores for upper extremity function (p = 0.001), strength of extensor carpi (p = 0.002), active ROM for wrist dorsiflexion (p = 0.003), activities of daily living score (p = 0.023) and ICF score (p < 0.001) than the NMES group at the endpoint. Conclusion: CCFES signifcantly shortened the time for regaining wrist dorsiflexion, and improved the upper extremity function and general health of patients with early-phase stroke. CCFES therefore has potential as a clinical intervention.

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