The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

Objective:To explore the prognostic factors of patients with advanced epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS).Methods:The clinical and pathological data of patients with stage Ⅲc-Ⅳ EOC underwent surgical treatment in Sichuan Cancer Center from January 1st, 2014 to December 31th, 2018 were retrospectively analyzed, and the prognosis was followed up.Results:(1) A total of 216 EOC patients were included in the study, whose age was (52.1±8.7) years old, the median follow-up time was 44.6 months (17.2-80.1 months), the median progression free survival (PFS) was 11.1 months (8.5-13.8 months), and the median overall survival (OS) was 40.0 months (32.7-47.3 months). (2) Among 216 patients with advanced EOC, there were 75 cases in the primary debulking surgery (PDS) group and 141 cases in the NACT+IDS group. Compared with the PDS group, the serum CA 125 level before treatment (median: 859.4 vs 1 371.0 kU/L), proportion of stage Ⅳ patients [5.3% (4/75) vs 23.4% (33/144)] and no visible residual disease (R0) cytoreduction rate in the NACT+IDS group were significantly higher [(41.3% (31/75) vs 61.7% (87/144); all P<0.05]. The median PFS in the NACT+IDS group was significantly shorter than that of the PDS group (9.1 vs 15.2 months; χ2=7.014, P=0.008), but there was no significant difference in the median OS between the two groups (42.6 vs 38.0 months; χ2=1.325, P=0.250). (3) Univariate analysis showed that body mass index (BMI), preoperative serum CA 125 level, surgical-pathological stage, NACT effect, postoperative residual tumor size, time to initiation of postoperative chemotherapy and chemotherapy regimen were significantly correlated with PFS in the NACT+IDS group (all P<0.05); preoperative serum CA 125 level, surgical-pathological stage, NACT effect, postoperative residual tumor size, postoperative chemotherapy regimen were significantly related with OS in the NACT+IDS group (all P<0.05). Multivariate analysis showed that BMI, postoperative residual tumor size, time to initiation of postoperative chemotherapy were independent factors of PFS in the NACT+IDS group (all P<0.05); preoperative serum CA 125 level, surgical-pathological stage, postoperative residual tumor size were independent factors of OS in the NACT+IDS group (all P<0.05). The results showed that the PFS of patients with normal preoperative serum CA 125 level and (or) chemotherapy ≤7 days after IDS was longer, while no significant difference comparable with those in the PDS group ( P>0.05), and OS was also showing an prolonged trend, but the difference was also not statistically significant ( P>0.05). Conclusions:Normal CA 125 before IDS and time received chemotherapy no longer than 7 days after IDS are two related factors of prognosis benefit in advance EOC patients treated with NACT+IDS. Therefore, timely adjustment of the dose and regimen of NACT to reduce CA 125 level to normal range in about three cycles before IDS, and strengthen IDS perioperative management to promote postoperative recovery and perform chemotherapy as soon as possible might help to improve the prognosis of patients.