CoNClUSIoN: There exists a hMTR4-PDIA3P1-miR-125/124-TRAF6 regulatory axis that regulates NF-κB signaling and chemoresistance, which may be exploited for anticancer therapy. (Hepatology 2020;71:1660-1677).L ong noncoding RNAs (lncRNAs) are nonprotein-coding transcripts of more than 200-nt in length. (1) The function of lncRNAs depends on their subcellular localization. (2) Nuclear lncRNAs may positively or negatively regulate gene expression by binding to DNA, RNA, or proteins and acting

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The biological functions of short open reading frame (sORF)‐encoded micropeptides remain largely unknown. Here, we report that LINC00998 , a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N‐nitrosodiethylamine‐induced hepatoma. Overexpression of the 5′UTR‐sORF sequence of LINC00998 , encoding wild‐type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single‐base deletion. Gain‐ and loss‐of‐function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated‐Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.

Previous studies have shown that matrine, a natural compound extracted from the herb Sophora flavescens, has a good anti-leukemia effect, but its key target and mechanism remains unclear. Here, we found that only c-Myc could respond rapidly to matrine treatment in three myeloid leukemia cell lines, and matrine inhibited both transcription and translation of c-Myc. Ribosome biogenesis and nucleotide metabolism, the key downstream of c-Myc, were significantly suppressed after matrine treatment. Therefore, our results confirmed that matrine is a special c-Myc inhibitor which suppresses ribosome biogenesis and nucleotide metabolism by inhibiting c-Myc in myeloid leukemia. This study provides scientific basis for the development of matrine derivatives to c-Myc-driven cancers.

Matrine is a main component extracted from legumes and has extensive anti-cancer effects, but its molecular mechanism is unclear. In our study, we found that matrine can induce vacuolation of leukemia cells, whose occurrence was closely related to inhibition of cell proliferation. Interestingly, the vacuolization was reversed after the removal of matrine. Matrine-induced vacuoles are acidic in nature, Transmission Electron Microscope (TEM) revealed that these vacuoles mainly derived from the lysosome, the vacuoles acquire some characteristics of lysosome (LAMP1). RNA-seq showed that the expression of vacuolation-related genes and lysosomal-related genes were up-regulated, and the two parts highly overlapped. Western Blot and FACS confirmed that matrine inhibits the expression and activity of intracellular proteolytic enzymes. RT-qPCR and Western Blot showed that matrine significantly up-regulated the expression levels of V-ATPase subunit genes in cells, and V-ATPase inhibitor significantly reversed the occurrence of cell vacuoles. It is suggested that V-ATPase plays an important role in matrine-induced vacuoles. The molecular structure of matrine was further analyzed, and the protonation of matrine in lysosomes to activate V-ATPase may be the direct cause of the vacuoles, and it is also a new molecular mechanism of matrine against the proliferation of leukemia cells.