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 thatSex-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 withinMAP4K4gene 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.

SRY‐box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell‐cycle‐arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2–Smad2/3–p53–p21^WAF1/CIP1–Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4–MAPK (JNK/ERK/p38)–ATF2 and WT1–ATF2 pathways, which is dependent on its high‐mobility group (HMG) domain. In addition, the SOX6‐induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT‐263 (navitoclax) and ABT‐199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6‐induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin‐resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1–ATF2–TGFβ2 axis mediates SOX6‐induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is a surrogate marker for reflecting the transcriptional activity of covalently closed circular DNA. However, there is still no standardized assay for the quantitative detection of serum HBV RNA in chronic hepatitis B patients. In this study, quantitative polymerase chain reactions for detecting the preC/C-RNA (preC/C region HBV pgRNA), SF-RNA (splicing variants-free pgRNA) and XR-RNA (X region remained pgRNA) regions were set up. The dynamic changes of serum pgRNA splicing variants and 3′ terminal truncations were analysed in three retrospective cohorts: 35 treatment-naive chronic HBV-infected patients (cohort A), 52 chronic hepatitis B (CHB) patients who received nucleos(t)ide analogs (NAs) therapy for 48 weeks (cohort B) and eight CHB patients who are under long-term NAs treatment (cohort C). The accuracy and sensitivity of HBV RNA detection were assessed by the National Standard of HBV RNA. We confirmed that high proportions of pgRNA splicing variants and 3′ terminal truncations were present and significantly affect the quantitative detection of serum HBV RNA in both treatment-naive and NAs-treated CHB patients. To achieve the higher accuracy and sensitivity on the detection of HBV RNA level, the primers and probes should be designed at the 5′ terminal region of HBV genome and outside the mainly spliced sequence of pgRNA, especially for CHB patients under long-term NAs treatment. This study would help to better understand the significance of the pgRNA splicing variants and 3′ terminal truncations, and further guide the clinical detection of serum HBV RNA.

Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance

Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells