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Hepatocellular carcinoma (HCC) is a type of malignant tumor with sixth highest incidence and causes the third most cancer-related deaths in the world, whose treatment is limited by the unclear molecular mechanism. Currently, the correlation between PSMC2 and HCC is still unclear. Herein, we found that the expression of PSMC2 in HCC tissues was significantly higher than normal tissues. We also discovered the significant association between PSMC2 expression and tumor infiltrate as well as tumor stage. Further investigations indicated that PSMC2 knockdown contributed to impaired proliferation, colony formation, migration, and enhanced cell apoptosis in HCC cells. Moreover, PSMC2 could also suppress tumorigenicity of HCC cells in vivo. Gene microarray analysis followed by ingenuity pathway analysis was performed for exploring downstream of PSMC2 and identified ITGA6 as a potential target. Furthermore, our study revealed that ITGA6 knockdown exhibited similar inhibitory effects with PSMC2 on HCC cells in vitro. More importantly, our results proved the direct interaction and showed the mutual regulation between PSMC2 and ITGA6, and that PSMC2 knockdown could significantly aggravate the inhibition of HCC by ITGA6 depletion. Based on these intriguing results, this is the first time ever that PSMC2 is pinpointed as a tumor promotor to interfere HCC development and progression via interacting with ITGA6 directly.

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Chemoresistance is a major factor contributing to the failure of cancer treatment. The conventional chemotherapy agent 5-fluorouracil (5-FU) has been used for cancer treatment for decades. However, its use is limited in the treatment of hepatocellular carcinoma (HCC) due to acquired resistance. Nrf2 (NF-E2-related factor 2) is known to be associated with drug resistance across a wide range of cancer types. Also, since arsenic trioxide (As 2 O 3 ) showed antitumor effects on HCC, the purpose of this study was to determine whether As 2 O 3 and Nrf2-siRNA could inhibit HCC synergistically. Methods: We generated two separate 5-FU-resistant HCC cell lines (SNU-387/5-FU and Hep3B/5-FU). Western blotting was used to determine protein levels. An efficient lentiviral delivery system was used to establish stable knockdown or overexpression of Nrf2 and HIF-1α. In vitro and in vivo analyses of the effects of Nrf2 gene knockdown and As 2 O 3 on 5-FU-resistant HCC cells were conducted. Results: The expression of Nrf2 was higher in the 5-FU-resistant HCC cell lines than in the parental cell lines. When coupled with Nrf2 knockdown, As 2 O 3 treatment significantly decreased 5-FU-resistant SNU-387 and Hep3B cell viability, migration, and invasion, inactivated HIF-1α/HSP70 signaling, inhibited anti-apoptotic B-cell lymphoma (Bcl-2) activity, and increased the expression of proapoptotic Bcl-2-associated X protein (BAX) along with caspase-3. The synergistic effect was also confirmed using a 5-FU-resistant Hep3B mouse xenograft model in vivo. Conclusion: Nrf2 knockdown could improve the effect of As 2 O 3 on reversing drug resistance in 5-FU-resistant HCC cells.

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