There are nearly 40% of cervical cancer patients showing poor response to neoadjuvant chemotherapy that can be induced by autophagy, however, the underlying mechanism has not yet been fully clarified. We previously found that Sex-determining region of Y-related high-mobility-group box 6 (SOX6), a tumor suppressor gene or oncogene in several cancers, could induce autophagy in cervical cancer. Accordingly, this study aims to investigate the mechanism of SOX6-induced autophagy and its potential significance in the platinum-based chemotherapy of cervical cancer. Firstly, we found that SOX6 could promote autophagy in cervical cancer cells depending on its HMG domain. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) gene was identified as the direct target gene of SOX6, which was transcriptionally upregulated by binding the HMG domain of SOX6 protein to its double-binding sites within MAP4K4 gene promoter. MAP4K4 mediated the SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR pathway and activating MAPK/ERK pathway. Further, the sensitivity of cervical cancer cells to cisplatin chemotherapy could be reduced by the SOX6-induced autophagy in vitro and in vivo, while such a phenomenon could be turned over by autophagy-specific inhibitor and MAP4K4 inhibitor, respectively. Moreover, cisplatin itself could promote the expression of endogenous SOX6 and subsequently the MAP4K4-mediated autophagy in cervical cancer cells, which might in turn reduce the sensitivity of these cells to cisplatin treatment. These findings uncovered the underlying mechanism and potential significance of SOX6-induced autophagy, and shed new light on the usage of MAP4K4 inhibitor or autophagy-specific inhibitor for sensitizing cervical cancer cells to the platinum-based chemotherapy.

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The HIV epidemic in China accounts for 3% of the global HIV incidence. We compared the patterns and determinants of interprovincial spread of the five most prevalent circulating types. HIV pol sequences sampled across China were used to identify relevant transmission networks of the five most relevant HIV-1 types (B, CRF01_AE, CRF07_BC, CRF08_BC and CRF55_01B) in China. From these, the dispersal history across provinces was inferred. A generalized linear model (GLM) was used to test the association between migration rates among provinces and several measures of human mobility. A total of 10,707 sequences between 2004-2017 across 26 provinces were collected, among which 1,962 newly reported here. A mean of 18 (Min-Max:1-54) independent transmission networks involving up to 17 provinces were identified. Discrete phylogeographic analysis largely recapitulate the documented spread of the HIV types which, in turn, to large extent mirror within-China population migration flows. In line with the different spatio-temporal spread dynamics, the identified drivers thereof were also heterogeneous but are consistent with a central role of human mobility. The comparative analysis of the dispersal dynamics of the five main HIV types circulating in China suggests a key role of large populations centers and developed transportation infrastructures as hubs of HIV dispersal. This advocates for coordinated public health efforts in addition to local targeted interventions. IMPORTANCE While traditional epidemiological studies are of great interest in describing the dynamics of epidemics, they cannot fully capture the geospatial dynamics and factors driving the dispersal of pathogens such as HIV as they struggle to capture linkages between infections. To overcome this, we used a discrete phylogeographic approach coupled to a generalized linear model extension to characterize the dynamics and drivers of the across-province spread of the five main HIV types circulating in China. Our results indicate that large urbanized areas with dense population and developed transportation infrastructures are facilitators of HIV dispersal throughout China, and highlight the need to consider harmonized country-wide public policies to control local HIV epidemics.