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Role of mitochondrial VDACs in liver cancer than the control cells. Our work suggesting that
VDACs are voltage-gated porins that are part of VDAC plays a significant role in liver tumour
the outer mitochondrial membrane. They can formation (both in vitro and in vivo). Towards
transport substrates, ions and nucleotides to exploring a regulatory axis, we zeroed in on a
mitochondria, and therefore play a very important particular miRNA, miR-29a, which is reportedly
role in integrating cytosolic processes and known to regulate VDAC expression. We could
mitochondrial functions within a cell. The role of establish that the miR-29-VDAC axis is functional
VDAC in general metabolism and in the regulation in liver cancer and our results prove that the
of cellular apoptosis has been reported in the past. tumour suppressive functions of miR-29 are
Metabolic rewiring towards glycolysis, and mediated, at least in part, via the functioning of
survival through suppression of apoptosis, are VDACs.
both hallmarks of a cancer cell. In the absence of
previous reports on how exactly VDAC might help MSCs in metabolic disorders
in tumorigenesis, we aimed to study its association Recent advances in mitochondrial therapeutics
and regulation in liver cancer. We found that the highlight the importance of Mesenchymal Stem
expression of VDAC1 and VDAC2 (functional Cell (MSCs) mediated mitochondrial donation in
isoforms) was increased in liver cancer. This the reversal of mitochondrial dysfunction
expression alteration was validated in three associated pathologies. MSCs isolated from
independent models: by analysing data from elderly/obese donors have been demonstrated to
human patient samples (LIHC cohort, TCGA,) in a have decreased biological activity. Whether basal
carcinogen-induced mouse model of liver tumour, mitochondrial functions are associated with this
as well as in cultured human cells. Overexpression lesser potential, we thought to study the
of VDACs in primary hepatocytes led to mitochondrial structure and function in
tumorigenic characteristics like increased metabolically altered obese subjects. We
proliferation, higher rate of cell division, generated a high fat diet induced obese mice
anchorage-independent cell growth and tumour model and isolated MSCs from their bone marrow
spheroid formation. We also found metabolic and compared their mitochondrial status with
rewiring in these cells by increased glycolytic MSCs from lean mice. Our data showed that obese
capacity. All these processes were subdued in liver MSCs have intrinsically higher ROS burden and
cancer cells by downregulating VDACs. We also more fragmented mitochondria. These MSCs had
found that this metabolic shift upon VDAC lower membrane potential and metabolic
manipulation is closely related to the expression of capacity. We also found that the mitochondrial
the cancer specific glycolytic enzyme Hexokinase- mass is more in MSCs of obese mice without
II. As role of several microRNAs are reported in having higher mitochondrial biogenesis. Further
tumorigenesis, we wanted to check whether mechanistic studies showed that the obese MSCs
VDACs are regulated by miRs in liver cancers. have less mitophagic clearance capacity which is
Previous reports showed that miR-29a could the cause of higher damaged mitochondrial mass,
target the 3’-UTR regions of both Vdac1 and Vdac2 increased ROS, less ATP and membrane potential
mRNAs. We found that indeed miR-29a is and fragmented mitochondria. Further, we
downregulated in liver cancers compared to its rescued these alterations in MSCs of obese mice
normal counterpart. By genetic manipulation of by treating them with a mitochondria targeting
miR-29a, we recapitulated all the tumorigenic drug Pyrroloquinoline quinone (PQQ). Previously
features mentioned above under in vitro we showed that mitochondrial donation from
conditions by using primary and cancerous liver healthy MSCs rescued the severity of asthmatic
cells. Importantly, tumours produced in nude mice mice. Now we are planning to rescue the obese
by xenografting liver cancer cells stably asthmatic mice either by feeding them with PQQ
overexpressing miR-29a were significantly smaller or by transferring PQQ treated MSCs into those
Annual Report 2020-21 134
